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  • Research Paper Volume 13, Issue 21 pp 24171-24191

    LncRNA OTUD6B-AS1 promotes paclitaxel resistance in triple negative breast cancer by regulation of miR-26a-5p/MTDH pathway-mediated autophagy and genomic instability

    Relevance score: 11.742513
    Peng-Ping Li, Rong-Guo Li, Yu-Qing Huang, Jin-Pian Lu, Wei-Jun Zhang, Zhen-Yu Wang
    Keywords: chemotherapy resistance, autophagy, genomic instability (GIN), triple negative breast cancer (TNBC), DNA damage response (DDR)
    Published in Aging on November 5, 2021
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    Genomic instability (GIN) is pivotal in regulating tumor drug resistance, which blocked the treatment of triple negative breast cancer (TNBC). Although recent studies implied that non-coding RNA (ncRNA)-mediated autophagy abolishment promoted tumorigenesis by up-regulation of GIN, autophagy was known as a risk factor in tumor drug resistance. However, previous study also pointed that up-regulation of autophagy promoted GIN. Therefore, the relationship between autophagy and GIN is not clear, and more work is needed. And, if an ncRNA is identified to be a co-regulator of autophagy and GIN, it will be a potential therapy target of chemotherapy resistance in TNBC. In our study, we recognized both autophagy-GIN-associated microRNA (mi-26a-5p) by big data analysis, which was prognosis-correlated in breast cancer. Next, we identified the up-stream regulators (long non-coding RNA, lncRNA) and down-stream targets of miR-26a-5p by bioinformatics analysis (online public databases). Finally, we established lncRNA OTUD6B-AS1/miR-26a-5p/MTDH signaling pathway, and verified their functions by cytological, molecular biological and zoological experiments. In general, our study found (1) miR-26a-5p was a protective factor of breast cancer, while OTUD6B-AS1 and MTDH were risk factors; (2) OTUD6B-AS1 was the up-stream regulator of miR-26a-5p verified by luciferase; (3) up-regulation of miR-26a-5p and down-regulation of MTDH promoted cellular cytotoxicity of paclitaxel (PTX) in vitro and in vivo. (4) down-regulation of miR-26a-5p, overexpression of MTDH and OTUD6B-AS1 promoted autophagy and DNA damage; (5) up-regulation of OTUD6B-AS1 and MTDH inhibited DNA damage response (DDR) by inhibiting the phosphorylated activation of RAD51, ATR and ATM.

  • Research Paper Volume 13, Issue 15 pp 19306-19316

    LncRNA-HAGLR motivates triple negative breast cancer progression by regulation of WNT2 via sponging miR-335-3p

    Relevance score: 14.071408
    Liting Jin, Chenggang Luo, Xinhong Wu, Manxiu Li, Shun Wu, Yaojun Feng
    Keywords: triple negative breast cancer, lncRNA HAGLR, miR-335-3p, WNT2, tumor progression
    Published in Aging on August 10, 2021
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    Background: Triple negative breast cancer (TNBC) is a group of highly heterogeneous mixed breast cancer at the level of gene expression profile. Therefore, it is of great clinical significance to explore the molecular mechanism of TNBC and find a targeted therapeutic approach from the molecular level.

    Methods: Long non-coding RNA (lncRNA) HAGLR expression level was measured by and qRT-PCR in TNBC tissues and cell lines. EdU, MTT, wound healing and Transwell assays were performed to explore the role of HAGLR on the malignancy of TNBC cells. Luciferase assay was used to clarify the binding between miR-335-3p with HAGLR and WNT2. The tumor formation experiment in nude mice was used to explore the function of HAGLR in vivo.

    Results: HAGLR was increased in TNBC tissues and cell lines. Silencing of HAGLR inhibited viability, proliferation, migration, and invasion of BT549 cells. Furthermore, HAGLR acted as a sponge of miR-335-3p and inhibited its expression. And miR-335-3p directly targeted WNT2. Functionally, forced expression of miR-335-3p or knockdown of WNT2 removed the promoted effects of lncRNA HAGLR on TNBC development. In vivo tumorigenesis experiments indicated HAGLR accelerated tumor growth via miR-335-3p/WNT2 axis.

    Conclusion: Our study revealed that HAGLR promoted the growth of TNBC, which was mediated by miR-335-3p/WNT2 axis.

  • Research Paper Volume 13, Issue 15 pp 19486-19509

    A combined hypoxia and immune gene signature for predicting survival and risk stratification in triple-negative breast cancer

    Relevance score: 17.411417
    Xia Yang, Xin Weng, Yajie Yang, Meng Zhang, Yingjie Xiu, Wenfeng Peng, Xuhui Liao, Meiquan Xu, Yanhua Sun, Xia Liu
    Keywords: triple-negative breast cancer, risk stratification, hypoxia, immune, survival
    Published in Aging on August 2, 2021
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    Background: Increasing evidence showed that the clinical significance of the interaction between hypoxia and immune status in tumor microenvironment. However, reliable biomarkers based on the hypoxia and immune status in triple-negative breast cancer (TNBC) have not been well established. This study aimed to explore a gene signature based on the hypoxia and immune status for predicting prognosis, risk stratification, and individual treatment in TNBC.

    Methods: Hypoxia-related genes (HRGs) and Immune-related genes (IRGs) were identified using the weighted gene co-expression network analysis (WGCNA) method and the single-sample gene set enrichment analysis (ssGSEA Z-score) with the transcriptomic profiles from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. Then, prognostic hypoxia and immune based genes were identified in TNBC patients from the METABRIC (N = 221), The Cancer Genome Atlas (TCGA) (N = 142), and GSE58812 (N = 107) using univariate cox regression model. A robust hypoxia-immune based gene signature for prognosis was constructed using the least absolute shrinkage and selection operator (LASSO) method. Based on the cross-cohort prognostic hypoxia–immune related gene signature, a comprehensive index of hypoxia and immune was developed and two risk groups with distinct hypoxia–immune status were identified. The prognosis value, hypoxia and immune status, and therapeutic response in different risk groups were analyzed. Furthermore, a nomogram was constructed to predict the prognosis for individual patients, and an independent cohort from the gene expression omnibus (GEO) database was used for external validation.

    Results: Six cross-cohort prognostic hypoxia–immune related genes were identified to establish the comprehensive index of hypoxia and immune. Then, patients were clustered into high- and low-risk groups based on the hypoxia–immune status. Patients in the high-risk group showed poorer prognoses to their low-risk counterparts, and the nomogram we constructed yielded favorable performance to predict survival and risk stratification. Besides, the high-risk group had a higher expression of hypoxia-related genes and correlated with hypoxia status in tumor microenvironment. The high-risk group had lower fractions of activated immune cells, and exhibited lower expression of immune checkpoint markers. Furthermore, the ratio of complete response (CR) was greatly declined, and the ratio of breast cancer related events were significantly elevated in the high-risk group.

    Conclusion: The hypoxia–immune based gene signature we constructed for predicting prognosis was developed and validated, which may contribute to the optimization of risk stratification for prognosis and personalized treatment in TNBC patients.

  • Research Paper Volume 13, Issue 14 pp 18191-18222

    Formononetin relieves the facilitating effect of lncRNA AFAP1-AS1-miR-195/miR-545 axis on progression and chemo-resistance of triple-negative breast cancer

    Relevance score: 14.204147
    Jingjing Wu, Wen Xu, Lina Ma, Jiayu Sheng, Meina Ye, Hao Chen, Yuzhu Zhang, Bing Wang, Mingjuan Liao, Tian Meng, Yue Zhou, Hongfeng Chen
    Keywords: lncRNA AFAP1-AS1, miR-195/miR-545, triple-negative breast cancer, formononetin, chemo-resistance
    Published in Aging on July 21, 2021
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    This investigation attempted to discern whether formononetin restrained progression of triple-negative breast cancer (TNBC) by blocking lncRNA AFAP1-AS1-miR-195/miR-545 axis. We prepared TNBC cell lines (i.e. MDA-MB-231 and BT-549) and normal human mammary epithelial cell line (i.e. MCF-10A) in advance, and the TNBC cell lines were, respectively, transfected by pcDNA3.1-lncRNA AFAP1-AS1, si-lncRNA AFAP1-AS1, pcDNA6.2/GW/EmGFP-miR-545 or pcDNA6.2/GW/EmGFP-miR-195. Resistance of TNBC cells in response to 5-Fu, adriamycin, paclitaxel and cisplatin was evaluated through MTT assay, while potentials of TNBC cells in proliferation, migration and invasion were assessed via CCK8 assay and Transwell assay. Consequently, silencing of lncRNA AFAP1-AS1 impaired chemo-resistance, proliferation, migration and invasion of TNBC cells (P<0.05), and over-expression of miR-195 and miR-545, which were sponged and down-regulated by lncRNA AFAP1-AS1 (P<0.05), significantly reversed the promoting effect of pcDNA3.1-lncRNA AFAP1-AS1 on proliferation, migration, invasion and chemo-resistance of TNBC cells (P<0.05). Furthermore, CDK4 and Raf-1, essential biomarkers of TNBC progression, were, respectively, subjected to target and down-regulation of miR-545 and miR-195 (P<0.05), and they were promoted by pcDNA3.1-lncRNA AFAP1-AS1 at protein and mRNA levels (P<0.05). Additionally, formononetin significantly decreased expressions of lncRNA AFAP1-AS1, CDK4 and Raf-1, while raised miR-195 and miR-545 expressions in TNBC cells (P<0.05), and exposure to it dramatically contained malignant behaviors of TNBC cells (P<0.05). In conclusion, formononetin alleviated TNBC malignancy by suppressing lncRNA AFAP1-AS1-miR-195/miR-545 axis, suggesting that molecular targets combined with traditional Chinese medicine could yield significant clinical benefits in TNBC.

  • Research Paper Volume 13, Issue 13 pp 17177-17189

    Carbon nanotubes (CNT)-loaded ginsenosides Rb3 suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer

    Relevance score: 15.333985
    Xiao Luo, Hui Wang, Degang Ji
    Keywords: triple-negative breast cancer, progression, CNTs, Rg3, PD-1/PD-L1 axis
    Published in Aging on June 10, 2021
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    Carbon nanotubes (CNTs), as advanced nanotechnology with specific properties and structures, have presented practical drug delivery properties. Ginsenoside Rg3 is a component of puffed ginseng and demonstrates anti-cancer activities. To explore the effect of CNTs-loaded Rg3 (Rg3-CNT) on the PD-1/PD-L1 signaling and the development of triple-negative breast cancer (TNBC). Our data revealed that Rg3 inhibited the cell viability of TNBC cells, in which Rg3-CNT further enhanced this effect in the system. Similarly, the colony formation of TNBC cells was decreased by Rg3, while Rg3-CNT could reinforce its effect in the cells. Besides, the treatment of Rg3 induced apoptosis of TNBC cells, in which Rg3-CNT treatment further increased the phenotype in the cells. Remarkably, Rg3-CNT, but not Rg3, attenuated PD-L1 expression in TNBC cells. Rg3-CNT decreased the PD-L1 upregulation induced by interferon-γ (IFN-γ) in breast cancer cells. Importantly, Rg3-CNT was able to reduce PD-1 expression in activated T cells. Specifically, Rg3-CNT reduced the PD-1/PD-L1 axis in a T cell/triple-negative TNBC cell co-culture system. Moreover, the levels of IFN-γ, interleukins-2 (IL-2), interleukins-9 (IL-9), interleukins-10 (IL-10), interleukins-22 (IL-22), and interleukins-23 (IL-23) were significantly stimulated in the activated T cells, while the treatment of Rg3-CNT could reverse these phenotypes in the cells. Rg3-CNT attenuated the TNBC cell growth in vivo. The Rg3-CNT improved the anti-cancer effect of Rg3 toward TNBC by inhibiting the PD-1/PD-L1 axis. Our finding provides new insights into the mechanism by which Rg3-CNT attenuates the development of TNBC. Rg3-CNT may be applied as the potential therapeutic strategy for immunotherapy of TNBC.

  • Research Paper Volume 13, Issue 9 pp 12514-12525

    Capsanthin induces G1/S phase arrest, erlotinib-sensitivity and inhibits tumor progression by suppressing EZH2-mediated epigenetically silencing of p21 in triple-negative breast cancer cells

    Relevance score: 15.465921
    Jia-Yan Wu, Yi-Chung Chien, I-Chen Tsai, Chih-Chiang Hung, Wei-Chien Huang, Liang-Chih Liu, Yung-Luen Yu
    Keywords: capsanthin, triple-negative breast cancer (TNBC), EZH2, p21, erlotinib
    Published in Aging on May 2, 2021
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    Capsanthin is a naturally occurring red pepper carotenoid with possible antitumor activity, but its antitumor mechanisms have yet to be delineated. We tested the anti-proliferative activity of capsanthin with human triple-negative breast cancer (TNBC) and found that cell proliferation was inhibited after 24, 48 and 72 h of treatment. We also investigated the cellular and molecular mechanisms of the antitumor efficacy of capsanthin on TNBC cells and found that capsanthin delayed cell-cycle progression at the G1/S stage, that cyclin A expression was suppressed, and that p21 expression was upregulated. Capsanthin also inhibited the EZH2 expression and EZH2 could binding to the p21 promoter in TNBC cells. We further discovered that capsanthin has synthetic effects when combined with erlotinib (Tarceva). In the animal experiment, we found that the capsanthin-induced inhibition of TNBC cell proliferation decreased the incidence of the initiation and growth of TNBC cell–derived tumors in mice. Our study reveals that capsanthin exerted antitumor effects through delaying cell-cycle progression, induces erlotinib-sensitivity and inhibits tumor progression by inhibiting EZH2/p21 axis, and capsanthin is a potential drug candidate for development of a safe and effective therapy against TNBCs, especially for TNBCs that have developed resistance to targeting therapy.

  • Research Paper Volume 13, Issue 5 pp 7211-7227

    Follistatin-like 1 deficiency impairs T cell development to promote lung metastasis of triple negative breast cancer

    Relevance score: 11.3382845
    Jie Ma, Ying Yang, Lulu Wang, Xiaowei Jia, Tao Lu, Yiyan Zeng, Li Liu, Yan Gao
    Keywords: follistatin-like 1, lung metastasis, triple negative breast cancer, thymus medullary epithelial cells, T cell development
    Published in Aging on February 26, 2021
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    Our study aims to detect the underlying mechanism of the suppressive effect of Follistatin-like 1 (FSTL1) on lung metastasis of triple negative breast cancer (TNBC). We found that FSTL1 had no effect on the proliferation and metastasis of 4T1 cells in vitro, while in the tumor-bearing Fstl1 heterozygous (Fstl1+/-) mice, the number of anti-tumor T lymphocytes in the lung was significantly reduced with the increase in lung metastasis. Impaired development of T cells can cause dysfunction of adaptive immune system, which promotes cancer metastasis. Therefore the effect of FSTL1 on T cell development was further investigated.

    Lower population of T cells in periphery and decreased proliferation of CD4- CD8- double negative (DN) thymocytes and impairment development of T cells were found in Fstl1+/- mice. Furthermore, high expression of FSTL1 in medullary thymus epithelial (mTEC) cells and decreased mRNA expression of inducible costimulator on activated T-cell ligand (Icosl) in mTECsh Fstl1 were detected. Combining other studies that the generation of ICOSL by mTEC cells promotes CD4+ single positive (SP) thymocytes to produce IL-2, which promotes T cell development. Our results indicate FSTL1 deficiency in mTEC cells impairs T cell development to promote the lung metastasis of TNBC.

  • Research Paper Volume 13, Issue 4 pp 5485-5505

    Tumor microenvironment characterization in triple-negative breast cancer identifies prognostic gene signature

    Relevance score: 17.060125
    Yan Qin, Jiehua Deng, Lihua Zhang, Jiaxing Yuan, Huawei Yang, Qiuyun Li
    Keywords: tumor microenvironment, triple-negative breast cancer, immune checkpoint
    Published in Aging on February 1, 2021
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    We aimed to elucidate the landscape of tumor microenvironment (TME) in triple-negative breast cancer (TNBC). Cohorts from Gene Expression Omnibus database (N = 107) and METABRIC (N = 299) were used as the training set and validation set, respectively. TME was evaluated via single-sample gene set enrichment analysis, and unsupervised clustering was used for cluster identification. Consequently, TNBC was classified into two distinct TME clusters (Cluster 1 and Cluster 2) according to predefined immune-related terms. Cluster 1 was characterized by low immune infiltration with poor prognosis; whereas, Cluster 2 was characterized by high immune infiltration with better survival probability. Further, Cluster 1 had larger tumor volumes, while Cluster 2 had smaller tumor volumes. Finally, a TME signature for prognosis stratification in TNBC was developed and validated. In summary, we comprehensively evaluated the TME of TNBC and constructed a TME signature that correlated with prognosis. Our results provide new insights for the immunotherapy of TNBC.

  • Research Paper Volume 13, Issue 3 pp 4522-4551

    Hsa_circ_0000199 facilitates chemo-tolerance of triple-negative breast cancer by interfering with miR-206/613-led PI3K/Akt/mTOR signaling

    Relevance score: 13.094165
    Hongchang Li, Wen Xu, Zhihua Xia, Weiyan Liu, Gaofeng Pan, Junbin Ding, Jindong Li, Jianfa Wang, Xiaofeng Xie, Daowen Jiang
    Keywords: hsa_circ_0000199, triple-negative breast cancer, miR-613, miR-206, PI3K/Akt/mTOR signaling
    Published in Aging on January 20, 2021
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    Increasing attentions have been paid to the role of circRNAs in the etiology of triple-negative breast cancer (TNBC), and we strived to figure out the association of circRNA AKT3/miRNA axis with TNBC chemo-resistance. Altogether 207 BC patients were divided into TNBC group (n=83) and non-TNBC group (n=124), and MCF-10A, MDA-MB-231, MDA-MB-468, SK-BR-3 and MCF-7 cell lines were prepared in advance. Expressions of AKT3-derived circRNAs and relevant miRNAs in the TNBC tissues and cell lines were determined by employing real-time polymerase chain reaction (PCR). It was indicated that hsa_circ_0000199 expression was higher in TNBC tissues than in non-TNBC tissues, and high hsa_circ_0000199 expression was predictive of large tumor size, advanced TNM grade, high Ki-67 level and poor 3-year survival of TNBC patients (all P<0.05). Furthermore, miR-613 and miR-206 were sponged and negatively regulated by hsa_circ_0000199 (P<0.001), and PI3K/Akt/mTOR signaling was depressed by si-hsa_circ_0000199 in TNBC cell lines (P<0.01). Ultimately, miR-206/miR-613 inhibitor reversed impacts of si-hsa_circ_0000199 on PI3K/Akt/mTOR signaling, proliferation, migration, invasion, chemo-sensitivity and autophagy of TNBC cells (all P<0.01). Conclusively, silencing of hsa_circ_0000199 enhanced TNBC chemo-sensitivity by promoting miR-206/miR-613 expression and deactivating PI3K/Akt/mTOR signaling, which was conducive to improving chemotherapeutic efficacy of TNBC patients.

  • Research Paper Volume 13, Issue 1 pp 228-240

    Downregulation of miR-155-5p enhances the anti-tumor effect of cetuximab on triple-negative breast cancer cells via inducing cell apoptosis and pyroptosis

    Relevance score: 15.571937
    Wen Xu, Changfeng Song, Xiaotong Wang, Yueqi Li, Xue Bai, Xin Liang, Jingjing Wu, Jianwen Liu
    Keywords: triple-negative breast cancer, microRNA 155-5p, cetuximab, apoptosis, pyroptosis
    Published in Aging on January 5, 2021
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    Cetuximab resistance is the main obstacle for the treatment of EGFR overexpression cancer, including triple-negative breast cancer (TNBC). MicroRNA (miRNA)-155-5p is upregulated in TNBC cells; thus, the present study explored whether the downregulation of miR-155-5p enhanced the anti-tumor effect of cetuximab in TNBC cells. MDA-MB-231 and MDA-MB-468 cells were infected with lentivirus-epidermal growth factor receptor (EGFR) for 72 h to obtain EGFR-overexpressed cell lines (MDA-MB-231 and MDA-MB-468). The inhibitory effects of cetuximab on the proliferation and migration of EGFR-overexpressed MDA-MB-468 cells were enhanced following transfection with the miR-155-5p antagomir, and miR-155-5p knockdown enhanced the pro-apoptotic effect of cetuximab on EGFR-overexpressed MDA-MB-468 cells. Further, the luciferase reporter assay revealed that gasdermin E (GSDME) was the direct binding target of miR-155-5p. The combination of cetuximab with the miR-155-5p antagomir promoted pyroptosis in EGFR-overexpressed MDA-MB-468 cells via the upregulation of GSDME-N and cleaved caspase-1. Results from the in vivo experiments confirmed that the downregulation of miR-155-5p enhanced the anti-tumor effect of cetuximab in an MDA-MB-468 xenograft model and on EGFR-overexpressed TNBC cells via inducing cell apoptosis and pyroptosis. Therefore, cetuximab combination with an miR-155-5p antagomir may be a novel therapeutic strategy for the treatment of TNBC.

  • Research Paper Volume 13, Issue 1 pp 1153-1175

    Construction of an mRNA-miRNA-lncRNA network prognostic for triple-negative breast cancer

    Relevance score: 15.465921
    Yuan Huang, Xiaowei Wang, Yiran Zheng, Wei Chen, Yabing Zheng, Guangliang Li, Weiyang Lou, Xiaojia Wang
    Keywords: triple-negative breast cancer, biomarker, competing endogenous RNA, prognosis
    Published in Aging on January 3, 2021
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    The aim of this study was to establish a novel competing endogenous RNA (ceRNA) network able to predict prognosis in patients with triple-negative breast cancer (TNBC). Differential gene expression analysis was performed using the GEO2R tool. Enrichr and STRING were used to conduct protein-protein interaction and pathway enrichment analyses, respectively. Upstream lncRNAs and miRNAs were identified using miRNet and mirTarBase, respectively. Prognostic values, expression, and correlational relationships of mRNAs, lncRNAs, and miRNAs were examined using GEPIA, starBase, and Kaplan-Meier plotter. It total, 860 upregulated and 622 downregulated differentially expressed mRNAs were identified in TNBC. Ten overexpressed and two underexpressed hub genes were screened. Next, 10 key miRNAs upstream of these key hub genes were predicted, of which six upregulated miRNAs were significantly associated with poor prognosis and four downregulated miRNAs were associated with good prognosis in TNBC. NEAT1 and MAL2 were selected as key lncRNAs. An mRNA-miRNA-lncRNA network in TNBC was constructed. Thus, we successfully established a novel mRNA-miRNA-lncRNA regulatory network, each component of which is prognostic for TNBC.

  • Research Paper Volume 13, Issue 1 pp 424-436

    LncRNA HAND2-AS1 suppressed the growth of triple negative breast cancer via reducing secretion of MSCs derived exosomal miR-106a-5p

    Relevance score: 14.181563
    Li Xing, Xiaolong Tang, Kaikai Wu, Xiong Huang, Yi Yi, Jinliang Huan
    Keywords: triple negative breast cancer, exosome, miR-106a-5p, MSCs, HAND2-AS1
    Published in Aging on December 3, 2020
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    Background: Triple-negative breast cancer (TNBC) is a special type of breast cancer, its tumor cell metastasis rate is much higher than other types, and at the same time has a high rate of postoperative recurrence, which significantly threatens the health of women. Thus, it is urgent to explore a new treatment for TNBC.

    Results: MiR-106a-5p was up-regulated in TNBC tissues and cells, and was positively correlated with the tumor grade, which indicated poor prognosis in TNBC patients. Mesenchymal stem cells (MSCs) can transport miR-106a-5p into TNBC cells via exosomes. Functional analysis showed exo-miR-106a-5p secreted by MSCs promoted tumor progression in TNBC cells. Furthermore, lncRNA HAND2-AS1 inhibited miR-106a-5p levels, and HAND2-AS1 was decreased in TNBC tissues and cells. Besides, overexpression of HAND2-AS1 reduced the secretion of exo-miR-106a-5p secretion from MSCs, thus suppressed TNBC development.

    Conclusion: Our study revealed that HAND2-AS1 inhibited the growth of TNBC, which were mediated by the inhibitory effects of MSC-derived exosomal miR-106a-5p.

  • Research Paper Volume 12, Issue 14 pp 14775-14790

    The circular RNA circEIF3M promotes breast cancer progression by promoting cyclin D1 expression

    Relevance score: 17.060125
    Xiujuan Li, Zhaojun Ren, Yufeng Yao, Jun Bao, Qiao Yu
    Keywords: circEIF3M, miR-33a, triple-negative breast cancer, CCND1
    Published in Aging on July 11, 2020
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    We investigated the function of circular RNA circEIF3M (hsa_circ_0003119) in triple-negative breast cancer. The expression profiles of circRNAs in 3 specimens of triple-negative breast cancer tissues with adjacent nontumor tissues were analyzed by RNA-sequencing. We verified the oncogenic role of circEIF3M in triple-negative breast cancer through a series of biological function experiments. It was found that circEIF3M was markedly upregulated in triple-negative breast cancer as compared to adjacent nontumor tissue, and that circEIF3M promoted triple-negative breast cancer cell proliferation, migration, and invasion. Mechanistic analysis indicated that circEIF3M may act as a competing endogenous RNA for miR-33a that relieves the inhibitory effect of miR-33a on its target cyclin D1. These findings showed that circEIF3M promotes triple-negative breast cancer progression via the circEIF3M/ miR-33a/ cyclin D1 axis.

  • Research Paper Volume 12, Issue 13 pp 13023-13037

    The Gαh/phospholipase C-δ1 interaction promotes autophagosome degradation by activating the Akt/mTORC1 pathway in metastatic triple-negative breast cancer

    Relevance score: 14.937864
    Hui-Yu Lin, Chia-Hao Kuei, Hsun-Hua Lee, Che-Hsuan Lin, Jing-Quan Zheng, Hui-Wen Chiu, Chi-Long Chen, Yuan-Feng Lin
    Keywords: gαh, autophagy, Akt/mTORC1, metastasis, triple-negative breast cancer
    Published in Aging on July 1, 2020
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    Lung metastasis (LM) is commonly found in triple-negative breast cancer (TNBC); however, the molecular mechanism underlying TNBC metastasis to lungs remains largely unknown. We thus aimed to uncover a possible mechanism for the LM of TNBC. Here we show that the phosphorylation of Akt and mTORC1 was positively but the autophagy activity was negatively correlated with endogenous Gαh levels and cell invasion ability in TNBC cell lines. Whereas the knockdown of Gαh, as well as blocking its binding with PLC-δ1 by a synthetic peptide inhibitor, in the highly invasive MDA-MB231 cells dramatically suppressed Akt/mTORC1 phosphorylation and blocked autophagosome degradation, the overexpression of Gαh in the poorly invasive HCC1806 cells enhanced Akt/mTORC1 phosphorylation but promoted autophagosome degradation. The pharmaceutical inhibition of autophagy initiation by 3-methyladenine was found to rescue the cell invasion ability and LM potential of Gαh-silenced MDA-MB231 cells. In contrast, the inhibition of mTORC1 activity by rapamycin suppressed autophagosome degradation but mitigated the cell invasion ability and LM potential of Gαh-overexpressing HCC1806 cells. These findings demonstrate that the induction of autophagy activity or the inhibition of Akt-mTORC1 axis provides a useful strategy to combat the Gαh/PLC-δ1-driven LM of TNBC.

    The mTORC1-related pathway is putatively activated in ER(-) breast cancer with high-level Gαh expression and lung metastasis. (A) Flowchart of the gene enrichment analysis (GSEA) using the transcription profiling of the top 10% upregulated and downregulated genes in ER(-) breast cancer tissues that were defined with low-level Gαh expression without lung metastasis or high-level Gαh expression with lung metastasis in a Kaplan-Meier analysis based on the GSE5327 data set. (B) The enrichment score (ES) derived from the correlation between the MTORC1 gene set and the queried gene signatures was plotted as the green curve. The parameters including the normalized enrichment score (NES), nominal p values and false discovery rates (FDRs) are shown as inserts. (C) Transcriptional profiling of the MTORC1 gene set in the groups is shown in A. The statistical significance was analyzed by Student’s t-test. (D) Correlation of the expression of Gαh mRNA levels and MTORC1 gene in the groups is shown in A. (E and F) Results from the Kaplan-Meier analyses of the transcriptional levels of the mTORC1 gene set alone (E) or combined with the mRNA levels of Gαh (F) against ER(-) breast cancer patients from the GSE5327 data set.



    The phosphorylation of Akt and mTORC1 positively correlates with cell invasion ability and is regulated by the Gαh-PLC-δ1 pathway in TNBC cells. (A) Results from the western blot analysis for the Gαh, phosphorylated Akt (p-Akt), Akt, p-mTOR, mTOR and GAPDH proteins derived from the indicated TNBC cell lines. (B) Giemsa staining of the invaded cells of the tested TNBC cell lines after a 16-hour invasion assay. (C) Correlation of mRNA expression levels between Gαh and the mTORC1 gene set in a panel of breast cancer cell lines derived from the Cancer Cell Line Encyclopedia (CCLE) database. Spearman’s correlation test was used to estimate the statistical significance. (D–E) Results from the western blot analysis for the Gαh, p-Akt, Akt, p-mTOR, mTOR and GAPDH proteins derived from the parental (PT) HCC1806 cells without (vector control, VC) or with Gαh overexpression (D) and the parental MDA-MD231 cells without (nonsilenced, NS) or with Gαh knocked down using two independent shRNA clones (E). (F–H) MDA-MD231 cells treated without or with 10 μM Gαh/PLC-δ1 protein-protein interaction (PPI) inhibitor for 2 hours were subjected to a reciprocal immunoprecipitation for detecting the PPI of Gαh/PLC-δ1 (F), Western blot analysis for measuring the protein levels of p-Akt, Akt, p-mTOR, mTOR and GAPDH (G), and immunofluorescent staining for visualizing the intracellular protein levels of p-Akt and p-mTOR (H). In A, D, E, G, GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group.



    The Gαh-PLC-δ1 axis promotes autophagosome degradation in TNBC cells. (A) Results from the Western blot analysis for LC3-I/II, p62 and GAPDH proteins derived from the indicated TNBC cell lines. (B) Correlation of mRNA expression levels of Gαh and the autophagy-related gene set in a panel of breast cancer cell lines derived from the Cancer Cell Line Encyclopedia (CCLE) database. Spearman’s correlation test was used to estimate the statistical significance. (C–E) Results from the Western blot analysis of the LC3-I/II, p62 and GAPDH proteins derived from the parental (PT) HCC1806 cells without (vector control, VC) or with Gαh overexpression (C) and the parental MDA-MD231 cells without (nonsilenced, NS) or with Gαh knocked down using two independent shRNA clones (D), and MDA-MD231 cells treated without or with 10 μM Gαh/PLC-δ1 protein-protein interaction (PPI) inhibitor for 2 hours (E). In A, C, D, E, GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group.



    The inhibition of autophagy initiation by 3-MA rescues the metastatic potential of the Gαh-silenced MDA-MB231 cells in vitro and in vivo. (A) The results from the Western blot analysis for the LC3-I/II, p62 and GAPDH proteins derived from MDA-MD231 cells without (NS) or with Gαh knocked down (KD) in the absence or presence of the autophagy inhibitor 3-MA (3 or 10 mM). GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group. (B–C) Giemsa staining (B) and cell number (C) of the invaded MDA-MD231 cell variants shown in A. Data obtained from three independent experiments are presented as the mean ± SEM. Letters indicate the significant differences at p<0.01 analyzed by nonparametric Friedman test. (D and E) H&E stained lung tissues (D) and the number of lung tumor colonies tumors (E) derived from the mice (n=5) transplanted with MDA-MD231 cell variants, shown in A, through tail vein injection for 4 weeks. Tumors are shown in red circles. Statistical significance was determined by nonparametric Mann-Whitney U test.



    The inhibition of mTORC1 activity by rapamycin restores autophagy function but compromises the cellular invasion and lung metastatic abilities of Gαh-overexpressing HCC1806 cells. (A) Results from the Western blot analysis of the LC3-I/II, p62 and GAPDH proteins derived from HCC1806 cells without (VC) or overexpression Gαh (OE) in the absence or presence of the mTOR inhibitor rapamycin (RAPA) (30 or 100 μM). GAPDH was used as an internal control of protein loading. The protein intensities of representative blots from three independent experiments were normalized by GAPDH levels and presented as a ratio to the control group. (B–C) Giemsa staining (B) and cell number (C) for the invaded HCC1806 cell variants shown in A. Data obtained from three independent experiments are presented as the mean ± SEM. Letters indicate the significant differences at p<0.01 analyzed by nonparametric Friedman test. (D and E) H&E staining of lung tissues (D) and the number of lung tumor colonies (E) derived from mice (n=5) transplanted with the HCC1806 cell variants, shown in A, through tail vein injection for 4 weeks. Tumors are shown in red circles. Statistical significance was analyzed by nonparametric Mann-Whitney U test.



    The signature of the combined Gαh upregulation and low levels of autophagy activity increases the likelihood of lung metastasis in ER(-) breast cancer patients. (A) Transcriptional profiling of the autophagy-related gene set in the groups shown in Figure1A. The statistical significance was analyzed by Student’s t-test. (B) Correlation of the expression levels of Gαh mRNA and the autophagy-related gene set in the stratified groups. (C and D) Results from the Kaplan-Meier analyses for the transcriptional level of the autophagy-related gene set alone (G) or combined with the mRNA level of Gαh (D) against ER(-) breast cancer patients from the GSE5327 data set.



  • Research Paper Volume 12, Issue 11 pp 10983-11003

    The circRNA circIFI30 promotes progression of triple-negative breast cancer and correlates with prognosis

    Relevance score: 15.969981
    Lei Xing, Rui Yang, Xiaosong Wang, Xiaying Zheng, Xin Yang, Luyu Zhang, Rong Jiang, Guosheng Ren, Junxia Chen
    Keywords: circIFI30, miR-520b-3p, triple-negative breast cancer, CD44
    Published in Aging on June 4, 2020
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    Growing evidence suggests that circRNAs exert a critical role in tumorigenesis and cancer progression. To date, the molecular mechanisms underlying circRNAs in triple-negative breast cancer (TNBC) are still poorly known. Here, circRNA expression profile was investigated by RNA sequencing in TNBC tissues and matched para-carcinoma tissues. We found that circIFI30 was significantly up-regulated in TNBC tissues and cells using quantitative real-time PCR and in situ hybridization. High circIFI30 expression was positively correlated with clinical TNM stage, pathological grade and poor prognosis of TNBC patients. Functionally, a series of in vivo and in vitro experiments showed that knockdown of circIFI30 could markedly inhibit TNBC cell proliferation, migration, invasion and cell cycle progression, induce apoptosis as well as suppress tumorigenesis and metastasis. Up-regulation of circIFI30 exerted an opposite effect. Mechanistically, we demonstrated that circIFI30 might act as a competing endogenous RNA (ceRNA) of miR-520b-3p to abolish the suppressive effect on target gene CD44 by fluorescent in situ hybridization (FISH), dual luciferase reporter assay, RNA immunoprecipitation and RNA pull-down assays. Therefore, our work uncovers the mechanism by which circIFI30 could promote TNBC progression through circIFI30/miR-520b-3p/CD44 axis and circIFI30 could be a novel diagnostic/prognostic marker and therapeutic target for TNBC patients.

    Expression profile of circRNA in TNBC and para-carcinoma tissues by RNA sequencing and characterization of circIFI30. (A) Hierarchical cluster analysis of all target circRNAs in the TNBC and matched para-carcinoma tissues was shown. Each column represents a sample and each row represents a circRNA. Red strip represents high relative expression and green strip represents low relative expression. (B) The cluster heat map showed the top 10 up-regulated and down-regulated circRNAs. (C) The genomic locus of the circIFI30 and the back-spliced junction of circIFI30 were indicated, the back-splice junction sequence was validated by Sanger sequencing. (D) PCR product of circIFI30 was confirmed by agarose gel electrophoresis. (E) CircIFI30, linear IFI30 and GAPDH were amplified from cDNA or gDNA in MDA-MB-231 cells with divergent and convergent primers, respectively. Divergent primers amplified circIFI30 in cDNA but not genomic DNA (gDNA). (F) RNase R treatment was used to evaluate the exonuclease resistance of circIFI30 in MDA-MB-231 cells. GAPDH was measured as a control. (G) Nuclear-cytoplasmic fractionation assay showed that circIFI30 was mainly localized in the cytoplasm of MDA-MB-231 cells. GAPDH was considered as a cytoplasmic control. U6 was used as a nuclear control.



    circIFI30 is up-regulated in TNBC and associated with the progression and poor prognosis of TNBC patients. (A) Relative expression of circIFI30 in TNBC tissues and adjacent non-tumor tissues was detected by qRT-PCR (n = 38). (B) Relative expression of circIFI30 in cell lines was determined by qRT-PCR. (C) ROC curve was applied to evaluate the diagnostic value of circIFI30 for TNBC. (D) Representative images of circIFI30 expression in TNBC tissues were detected by ISH assays. Scale bar, 100 μm. (E) Dot distribution graph of circIFI30 ISH staining scores was shown in TNBC patients with different pathological grades. (F) Kaplan-Meier survival curve of overall survival in 78 patients with TNBC according to the circIFI30 expression. Patients were stratified into high expression and low expression group by median expression. Data were showed as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.



    circIFI30 promotes TNBC cell proliferation. (A) Relative expression of circIFI30 was determined in TNBC cells transfected with circIFI30 expression vector, mock, sh-circ or sh-NC by qRT-PCR. (B) The cell viability was measured in TNBC cells transfected with indicated vectors by CCK-8 assay. (C, D) The cell proliferation ability was detected in TNBC cells after transfection with indicated plasmids by EdU assay. Scale bar, 50 μm. (E, F) Cell survival was evaluated in TNBC cells transfected with indicated plasmids by colony formation assay. Data were showed as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.



    circIFI30 increases TNBC cell migration and invasion and modulates cell cycle and apoptosis. (A, B) The cell migration capacity was detected by wound healing assay after transfection with indicated vectors (magnification, × 50). Scale bar, 200 μm. (C, D) The cell invasion ability was determined by transwell assay after overexpression or knockdown of circIFI30 (magnification, × 100). Scale bar, 100 μm. (E, F) The cell cycle progression was analyzed by flow cytometry after transfected with indicated plasmids. (G, H) The apoptosis rate detected by flow cytometry after downregulation of circIFI30. (I, J) The apoptotic cells were observed by Hoechst 33342 (magnification, ×100, scale bar, 100 μm) and TUNEL staining (magnification, × 100, scale bar, 100 μm) assays after knockdown of circIFI30. (K) The expression levels of apoptosis-related proteins were determined by western blot. Data were showed as mean ± SD, *P < 0.05, **P < 0.01.



    circIFI30 facilitates tumorigenesis and metastasis of TNBC cells in vivo. (A, B) Representative images of xenograft tumors of each group and tumor weight analysis were shown. (C) Growth curves of xenograft tumors were measured once a week. (D, E) HE staining of tumor and lung sections were showed. The microvessels of the tumors and metastatic nodules of the lungs were indicated by arrows (magnification, × 100, scale bar, 100 μm). (F) IHC staining was applied to analyze the protein levels of CD44 and EMT-related molecules (magnification, × 200, scale bar, 100 μm). Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.



    circIFI30 functions as a sponge for miR-520b-3p. (A) The miR-520b-3p binding site on circIFI30 was predicted by targetScan and miRanda. (B) FISH was performed to observe the cellular location of circIFI30 in TNBC cells (magnification, × 200, scale bar, 50 μm) and tissues (magnification, × 100, scale bar, 50 μm). (C) Relative expression of miR-520b-3p in TNBC tissues and adjacent non-tumor tissues was determined by qRT-PCR (n = 38). (D) Schematic illustration of circIFI30-WT and circIFI30-Mut luciferase reporter vectors was shown. (E) The relative luciferase activities were detected in 293 T cells after transfection with circIFI30-WT or circIFI30-Mut and miR-520b-3p mimics or miR-NC, respectively. (F, G) Anti-AGO2 RIP was executed in MDA-MB-231 cells after transfection with miR-520b-3p mimic or miR-NC, followed by western blot and qRT-PCR to detect AGO2 protein, circIFI30 and miR-520b-3p, respectively. (H) RNA pull-down with a biotin-labeled circIFI30 probe was executed in MDA-MB-231 cells, followed by qRT-PCR and RT-PCR to detect the enrichment of circIFI30 and miR-520b-3p. (I) The relative expression of miR-520b-3p was detected by qRT-PCR after transfection with indicated vectors. Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.



    circIFI30 promotes cell proliferation, migration and invasion through circIFI30/miR-520b-3p/CD44 axis. (A) The cell viability was determined after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by CCK8 assay. (B, C) The cell proliferation was detected after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by EdU assay (magnification, × 100, scale bar, 100 μm). (D, E) The cell survival was measured after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by colony formation assay. (F, G) The cell migration capacity was detected after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by wound healing assays (magnification, × 50). Scale bar, 200 μm. (H, I) The cell invasion ability was determined after transfection with indicated vectors, miR-520b-3p mimics or inhibitors by transwell assays (magnification, × 100, scale bar, 100 μm). (J, K) Relative expressions of CD44 and EMT-related molecules at protein level in cells transfected with indicated vectors, miR-520b-3p mimics or inhibitors were determined by western blot. Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.



    CD44 is directly targeted by miR-520b-3p and regulated by circIFI30. (A) Schematic illustration of CD44 3’UTR-WT and CD44 3’UTR-Mut luciferase reporter vectors was shown. (B) Luciferase reporter assay demonstrated that CD44 is direct target of miR-520b-3p. (C, D) Relative mRNA and protein levels of CD44 were detected after TNBC cells were transfected with miR-520b-3p mimics or inhibitors using qRT-PCR and western blot, respectively. (E) Pearson correlation analysis between the expression of circIFI30 and CD44 was shown in 38 TNBC tissues. (F) Relative expression of CD44 was detected by qRT-PCR in cells transfected with indicated vectors, miR-520b-3p or inhibitors. (G) The schematic diagram illustrates how circifi30 might promote EMT, tumorigenesis and metastasis of TNBC through circIFI30/miR-520b-3p/CD44 axis. Data were indicated as mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.



  • Research Paper Volume 12, Issue 10 pp 9621-9632

    Pyrrolo [3,4-b]-quinolin-9-amine compound FZU-0038-056 suppresses triple-negative breast cancer partially through inhibiting the expression of Bcl-2

    Relevance score: 13.69559
    Danping Wang, Zhi Nie, Xiaoyan Jiang, Jinxiang Ye, Zhimin Wei, Dating Cheng, Chenyang Wang, Yingying Wu, Rong Liu, Haijun Chen, Ceshi Chen, Chunyan Wang
    Keywords: triple-negative breast cancer, tetrahydro-β-carboline derivatives, apoptosis, Bcl-2
    Published in Aging on May 23, 2020
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    Triple-negative breast cancer (TNBC) has a poorer prognosis than other subtypes of breast cancer; however, it lacks effective targeted therapies clinically. In this study, we found FZU-0038-056, a novel compound derived from last-stage functionalization of tetrahydro-β-carboline scaffold, showed the most potent anti-cancer activity against TNBC cells among the 42 synthesized derivatives. We found FZU-0038-056 significantly induces apoptosis in HCC1806 and HCC1937 TNBC cells. FZU-0038-056 reduces the expression levels of several anti-apoptosis proteins, including Bcl-2, Mcl-1 and XIAP. Furthermore, we found FZU-0038-056 induces apoptosis partially through inhibiting the expression of Bcl-2. Finally, we found FZU-0038-056 significantly suppresses HCC1806 xenograft tumor growth in nude mice without affecting their body weight. Therefore, FZU-0038-056 has the potential to be a new anticancer agent for treating human TNBC.

    Identification of FZU-0038-056 as a potent anti-cancer compound in TNBC cell lines. (A) The HCC1806 and HCC1937 breast cancer cell lines were treated with 42 different compounds (10 μM) for 48 hours. DMSO was used as the negative control. Cell viability was measured using SRB assays. FZU-0038-056 and FZU-0038-058 labeled with an asterisk were selected for further studies. (B) Four different TNBC cell lines, two ER positive breast cancer cell lines and one human immortalized breast cell line were treated with DMSO control or FZU-0038-056/FZU-0038-058 at indicated concentrations (2.5, 5 and 10 μM, respectively) for 48 hours. Cell viability was measured using SRB assay. (C) The chemical structures of FZU-0038-056 and FZU-0038-058.



    FZU-0038-056 induces apoptosis in HCC1806 and HCC1937 cells. (A) The cell morphology changes of HCC1806 and HCC1937 cells after the treatment of FZU-0038-056 (10μM) for 12 hours. (B) HCC1806 and HCC1937 cells were stained with Annexin V/PI and analyzed by flow cytometry analysis after the cells were treated with FZU-0038-056 (2.5, 5, 10 μM) for 24 hours. DMSO was added as the negative control. (C, D) The percentages of Annexin V-positive cells from panel B are shown. ** p < 0.01.



    FZU-0038-056 decreases the expression of anti-apoptosis proteins and increased p38 phosphorylation in HCC1806 and HCC1937 cells. (A) HCC1806 and HCC1937 cells were treated with FZU-0038-056 (2.5, 5, 10 μM) for 24 hours. Cell lysates were collected for immunoblotting to test the protein levels of cleaved Caspase-3, and PARP, Bcl-2, XIAP, Mcl-1; Bax, Bak and DR5. β-actin was used as the loading control. The quantification data of cl-caspase-3 and Bcl-2 protein expression were shown under the immunoblot images. (B) HCC1806 and HCC1937 cells were treated with FZU-0038-056 (2.5, 5, 10 μM) for 24 hours. The protein levels of p38, p-p38, AKT, p-AKT, ERK, p-ERK, JNK and p-JNK were examined by WB. GAPDH was used as the loading control. The quantification data of p-p38 protein expression was shown under the immunoblot images.



    FZU-0038-056 induces TNBC apoptosis not through activating p38. (A, B) HCC1806 and HCC1937 cells were transfected with siRNAs targeting p38 for 36 hours, and treated with FZU-0038-056 (5 μM) or DMSO for 24 hours. Cell lysates were collected for WB assay. The quantification data of p-p38 protein expression was shown under the immunoblot images. (C, D) HCC1806 and HCC1937 cells were transfected with siRNA for 36 hours, then treated with FZU-0038-056 (1.25, 2.5, 5 μM) or DMSO for 48 hours. Cell viability was measured via the SRB assay.



    FZU-0038-056 induced apoptosis partially via inhibiting Bcl-2 in HCC1806 cells. (A) Bcl-2 was overexpressed in HCC1806 cells through a lentivirus system. (B) Overexpression of Bcl-2 reduced the cell viability inhibition triggered by FZU-0038-056. Cell viability was measured by the SRB assay. *p < 0.05. (C) FZU-0038-056-induced apoptosis were partially rescued by the overexpression of Bcl-2 compared with the control cells, as measured by Annexin V staining and flow cytometry analysis. Annexin V positive cell populations were quantified and shown on the right side. *p < 0.05. (D) FZU-0038-056-induced apoptosis were partially rescued by the overexpression of Bcl-2, as measured by Caspase-3 and PARP cleavage. The cells were treated with DMSO or FZU-0038-056 (10 μM) for 24 hours, and cell lysates were collected for WB analysis. β-actin was used as loading control.



    FZU-0038-056 suppresses HCC1806 xenograft tumor growth in nude mice. (A) FZU-0038-056 suppresses HCC1806 xenograft tumor growth in nude mice. Tumors were collected after the mice were treated with FZU-0038-056, vehicle, or cisplatin for 20 days. (B) FZU-0038-056 significantly reduced HCC1806 xenograft weights. Average tumor weights are graphed (n=5). **p < 0.01. (C) Tumor growth was significantly suppressed by FZU-0038-056 (15 mg/kg) and cisplatin (8 mg/kg) compared with vehicle control. **p < 0.01, *p < 0.05. (D) Compared to vehicle control, FZU-0038-056 (15 mg/kg) did not significantly reduce the mouse body weights although cisplatin (8 mg/kg) reduced the mouse body weights significantly.



  • Research Paper Volume 12, Issue 4 pp 3594-3616

    LncRNA FAM83H-AS1 promotes triple-negative breast cancer progression by regulating the miR-136-5p/metadherin axis

    Relevance score: 13.148844
    Chunyong Han, Yiwei Fu, Ni Zeng, Jian Yin, Qian Li
    Keywords: triple-negative breast cancer (TNBC), FAM83H-AS1, miR-136-5p, metadherin (MTDH)
    Published in Aging on February 17, 2020
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    In this study, we evaluated the function and regulation of the long non-coding RNA (lncRNA) FAM83H-AS1 in triple-negative breast cancer (TNBC). Our data show that the FAM83H-AS1 levels are increased in human TNBC cells and tissues. Proliferation, migration, and invasion of TNBC cells are decreased by FAM83H-AS1 suppression, but increased by FAM83H-AS1 overexpression. Bioinformatics analysis revealed that miR-136-5p is a potential target of FAM83H-AS1. MiR-136-5p expression is decreased in TNBC tissues, and its overexpression suppresses TNBC cell proliferation, migration, and invasion. MiR-136-5p suppression reverses the FAM83H-AS1 silencing-mediated inhibition of TNBC cell proliferation, migration, and invasion, suggesting that FAM83H-AS1 exerts its oncogenic effect by inhibiting miR-136-5p. Our data identify metadherin (MTDH) as the target gene of miR-136-5p, and demonstrate that the MTDH expression is increased in human TNBC tissues, which induces proliferation, migration, and invasion of TNBC cells. Importantly, our in vivo data show that FAM83H-AS1 also promotes tumor growth in TNBC mouse xenografts. Together, our results demonstrate that FAM83H-AS1 functions as an oncogenic lncRNA that regulates miR-136-5p and MTDH expression during TNBC progression, and suggest that targeting the FAM83H-AS1/miR-136-5p/MTDH axis may serve as a novel therapeutic target in TNBC.

    FAM83H-AS1 is upregulated in TNBC tissues and predicts worse overall survival. (A) Expression profiles of FAM83H-AS1 in TNBC and normal breast tissues using the human lncRNA microarray dataset GSE76250. The p value was calculated by Wilcoxon rank-sum test. (B) Expression profiles of FAM83H-AS1 in TNBC and normal breast tissues using the GEPIA 2 dataset. (C) Overall survival rates in low and high FAM83H-AS1 expression groups in TNBC patients using the GEPIA2 dataset. (D) qRT-PCR of FAM83H-AS1 expression in human TNBC and adjacent control tissues. (E) qRT-PCR of FAM83H-AS1 mRNA in MDA-MB-231, MDA-MB-436, MDA-MB-468, and MCF-10A cells.



    FAM83H-AS1 suppression inhibits TNBC cell proliferation, migration, and invasion. (A) qRT-PCR of FAM83H-AS1 expression in TNBC cells transfected with si-control or si-FAM83H-AS1 RNA. (B, C) Proliferation of TNBC cells transfected with si-control or si-FAM83H-AS1 RNA, analyzed by CCK8 assay. (D, E) Wound healing assay of the migration capacity of MDA-MB-231 and MDA-MB-468 cells transfected with si-control or si-FAM83H-AS1. (F, G) Migration and invasion of MDA-MB-231 and MDA-MB-468 cells transfected with si-control or si-FAM83H-AS1. Scale bars, 100 μm. * p < 0.05 compared to controls.



    FAM83H-AS1 functions as a sponge for miR-136-5p. (A) Predicted binding site of miR-136-5p in the FAM83H-AS1 sequence and mutated nucleotides. (B, C) Overexpression of miR-136-5p repressed the luciferase activity in TNBC cells transfected with FAM83H-AS1-Wt assessed by luciferase reporter assays. (D) Relative FAM83H-AS1 expression in TNBC cells transfected with mimic control, miR-136-5p mimic, inhibitor control, or miR-136-5p inhibitor. (E) Relative miR-136-5p expression in TNBC cells transfected with si-control, si-FAM83H-AS1, pcDNA-control, or pcDNA-FAM83H-AS1. (F) qRT-PCR analysis of miR-136-5p expression in human TNBC and adjacent control tissues. (G) qRT-PCR analysis of miR-136-5p levels in TNBC cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-468, and a control breast epithelial cell line MCF-10A. (H) RIP assay demonstrating the enrichment of FAM83H-AS1 and miR-136-5p. * p < 0.05 compared to controls.



    Overexpression of miR-136-5p reduces TNBC cell proliferation, migration, and invasion. (A) Relative miR-136-5p expression in TNBC cells transfected with mimic control or miR-136-5p mimic. (B, C) Proliferation of TNBC cells transfected with mimic control or miR-136-5p mimic, analyzed by CCK8 assay. (D, E) Wound healing assay of the migration capacity of TNBC cells transfected with mimic control or miR-136-5p mimic. (F, G) Migration and invasion of TNBC cells transfected with mimic control or miR-136-5p mimic, analyzed by transwell assays. Scale bars, 100 μm. * p < 0.05 compared to controls.



    FAM83H-AS1 promotes TNBC cell proliferation, migration, and invasion through inhibiting miR-136-5p. (A) Relative miR-136-5p expression in TNBC cells transfected with control, si- FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor evaluated by qRT-PCR. (B, C) Proliferation of TNBC cells transfected with control, si-FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor, analyzed by CCK8 assay. (D, E) Wound healing assay of the migration of MDA-MB-231 and MDA-MB-468 cells transfected with control, si-FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor. (F, G) Migration and invasion of TNBC cells transfected with control, si-FAM83H-AS1, and si-FAM83H-AS1+miR-136-5p inhibitor, assessed by transwell assays. * p < 0.05 compared to controls.



    MiR-136-5p suppresses MTDH expression in TNBC cells. (A) Predicted binding site of miR-136-5p in MTDH sequence and mutated nucleotides. (B) MTDH expression in TNBC tissues analyzed using GEPIA 2 dataset. (C) qRT-PCR analysis of MTDH expression in human TNBC tissues. (D) qRT-PCR analysis of MTDH expression in MDA-MB-231, MDA-MB-436, MDA-MB-468, and MCF-10A cells. (E) MTDH expression in TNBC cells transfected with mimic control or miR-136-5p mimic. (F, G) Western blot analysis of MTDH protein levels in TNBC cells transfected with mimic control or miR-136-5p mimic. (H, I) Overexpression of miR-136-5p represses the luciferase activity in TNBC cells transfected with MTDH-Wt, evaluated by luciferase reporter assays. (J) Correlation between FAM83H-AS1 and MTDH expression in breast cancer tissues analyzed by Spearman’s rank test using the GEPIA 2 dataset. * p < 0.05 compared to controls.



    MiR-136-5p inhibits proliferation, migration, and invasion of TNBC cells through suppressing MTDH. (A, B) Western blot analyses in TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (C) Expression of MTDH in TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (D, E) CCK8 assay utilized to evaluate cell proliferation of TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (F, G) Wound healing assay used to determine migration of TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH. (H, I) Migration and invasion of TNBC cells transfected with mimic control, miR-136-5p mimic, or miR-136-5p mimic plus oeMTDH, analyzed by transwell assays. * p < 0.05 compared to controls.



    FAM83H-AS1 promotes tumor growth in TNBC xenograft mouse model. (A, B) Tumor volume measured every 5 days in mice injected with TNBC cells transfected with sh-control or sh-FAM83H-AS1. (C) Tumor weight in mice injected with TNBC cells transfected with sh-control or sh-FAM83H-AS1. (D, E) Tumor size measured in mice injected with TNBC cells transfected with LV-control or LV-FAM83H-AS1. (F) Tumor weight in mice injected with TNBC cells transfected with LV-control or LV-FAM83H-AS1. * p < 0.05 compared to controls.



  • Research Paper Volume 11, Issue 24 pp 12043-12056

    CircAHNAK1 inhibits proliferation and metastasis of triple-negative breast cancer by modulating miR-421 and RASA1

    Relevance score: 14.937864
    Weikai Xiao, Shaoquan Zheng, Yutian Zou, Anli Yang, Xinhua Xie, Hailin Tang, Xiaoming Xie
    Keywords: biomarker, triple negative breast cancer, circAHNAK1, miR-421, RASA1
    Published in Aging on December 19, 2019
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    Background: There is increasing evidence that circular RNAs (circRNAs) participate in regulating cancer progression. However, the function and potential molecular mechanisms of circRNA in triple negative breast cancer (TNBC) are currently largely unclear.

    Results: We found that circAHNAK1 was significantly down-regulated in TNBC, and its expression was negatively associated with RFS and OS. Overexpression of circAHNAK1 can inhibit TNBC proliferation, migration and invasion in vitro. In vivo studies confirmed that circAHNAK1 inhibited TNBC tumor growth and metastasis. Mechanistic analysis indicated that circAHNAK1 acted as a miR-421 ceRNA (competitive endogenous RNA) to attenuate the inhibitory effect of miR-421 on its target gene RASA1.

    Conclusions: In conclusion, CircAHNAK1 inhibits proliferation and metastasis of TNBC by modulating miR-421 and RASA1.

    Methods: CircRNA microarrays were used to screen for differential circRNA expression profiles. qRT-PCR was used to detect the expression levels of circRNAs. The effect of circAHNAK1 on recurrence -free survival (RFS) and overall survival (OS) in patients with TNBC was subsequently analyzed. The role of circAHNKA1 in the progression of TNBC was further evaluated by multiple in vivo and in vitro assays. Finally, we focused on the regulation of circAHNAK1 on miR-421 and its targeted gene RASA1 in TNBC.

    circANNAK1 is down-regulated and associated with malignant progression and poor prognosis of TNBC. (A) Expression of circAHNAK1 in breast cancer cell lines. (B) Expression of circAHNAK1 in breast cancer tissues and normal adjacent tissues. (C, D)The effect of circAHNAK1 expression on OS and DFS in patients with TNBC. *** P <0.001.



    Overexpression of circAHNAK1 inhibits proliferation and metastasis of TNBC. (A)Successfully established two breast cancer cell lines that overexpress circAHNAK1; (B) CCK-8 assay to evaluate the effect of circAHNAK1 on cell proliferation; (C) Colony formation assay to evaluate the effect of circAHNAK1 on cell colony forming ability; (D) Number of clones quantified by ImageJ; (E) Transwell invasion assay to evaluate the effect of circAHNAK1 on cell invasion; (F) ImageJ quantifies the number of invading cells; (G) Wound healing assay evaluates the effect of circAHNAK1 on wound closure; (H) ImageJ quantifies the extent of wound healing; (I) Xenograft model to evaluate the effect of circAHNAK1 on tumor proliferation in vivo; (J) Effect of circAHNAK1 on proliferation in vivo by tumor weight; (K) Representative images of luciferase signaling to assess the effects of circAHNAK1 on lung metastasis in vivo; (L) Representative images of HE staining of lung metastatic nodule sections; (M) Quantification of the number of lung metastatic nodules.



    circAHNAK1 can act as a sponge for miR-421. (A) The expression levels of nuclear control (18S), cytoplasmic control (β-actin) and circAHNAK1 were detected; (B) Prediction of the binding site of miR-421 in the circAHNAK1 sequence; (C) The expression of miR-421 in TNBC cell line; (D) Luciferase assay of cells co-transfected with the miR-421 mimics and the circ-AHNAK1 wild type or mutant luciferase reporter; (E) GFP-MS2-RIP assay detects enrichment of miR-421after MS2bs-circAHNAK1-WT, MS2bs-circAHNAK1-Mut or control transfection, respectively; (F) Effect of miR-421 mimics transfection on proliferation of circAHNAK1 overexpressing cells by CCK-8; (G) Effect of miR-421 mimics transfection on circAHNAK1 overexpressing cells by clone formation assay; (H) Quantitative clone formation by ImageJ software; (I) Transwell invasion assay assessed the impact on cell invasion;(J) ImageJ software quantifies the number of invading cells;(K)Wound healing assay for detecting changes in cell migration ability; (L) ImageJ software quantifies the extent of wound closure; (M) Xenograft model to evaluate tumor proliferation in vivo; (N) Comparison of tumor weight; (O)Representative images of luciferase signaling of lung metastasis in vivo; (P) Representative images of HE staining of lung metastatic nodule sections; (Q) Quantification of the number of lung metastatic nodules.



    circAHNAK1 acts as a ceRNA to regulate RASA1. (A)Predicting the binding site of miR-421 in the RASA1-3′UTR region by TargetScan;(B) Luciferase assay after transfection with miR-421 mimics or inhibitor (C) Detection of RASA1 expression after miR-421 transfection by qRT-PCR; (D) Detection of RASA1 expression after transfection by immunofluorescence; (E)Detection of RASA1 expression after transfection by western blots. (F)Ago2-RIP assay showed enrichment of circAHNAK1, RASA1 and miR-421 on Ago2; (G) Ago2-RIP assay showed the effect of circAHNAK1 overexpression on RASA1 enrichment; (H) qRT-PCR detected RASA1 expression after transfection of circAHNAK1 and/or miR-421; (I)Western blots detected RASA1 expression after transfection of circAHNAK1 and/or miR-421;



    RASA1 is down-regulated and associated with poor prognosis of TNBC. (A) qRT-PCR detected mRNA expression of RASA1 in breast cancer cell lines;(B)Western blots detected RASA1 expression in breast cancer cell lines;(C) Representative IHC images of high and low RASA1 expression in TNBC tissues;(D, E)The effect of RASA1 expression on OS and DFS in patients with TNBC.



  • Research Paper Volume 11, Issue 23 pp 11054-11072

    EGFR-specific CAR-T cells trigger cell lysis in EGFR-positive TNBC

    Relevance score: 12.57629
    Yan Liu, Yehui Zhou, Kuo-Hsiang Huang, Ying Li, Xujie Fang, Li An, Feifei Wang, Qingfei Chen, Yunchao Zhang, Aihua Shi, Shuang Yu, Jingzhong Zhang
    Keywords: triple-negative breast cancer, human epidermal growth factor receptor, chimeric antigen receptor engineered T cells
    Published in Aging on December 4, 2019
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    Triple-negative breast cancer (TNBC) is an aggressive cancer subtype for which effective therapies are lacking. Epidermal growth factor receptor (EGFR) is overexpressed in various types of TNBC cells, and several EGFR-specific immunotherapies have been used to treat cancer patients. Chimeric antigen receptor engineered T (CAR-T) cells have also been used as cancer therapies. In this study, we generated two types of EGFR-specific CAR-modified T cells using lentiviral vectors with DNA sequences encoding the scFv regions of two anti-EGFR antibodies. The cytotoxic and antitumor effects of these CAR-modified T cells were examined in cytokine release and cytotoxicity assays in vitro and in tumor growth assays in TNBC cell line- and patient-derived xenograft mouse models. Both types of EGFR-specific CAR-T cells were activated by high-EGFR-expressing TNBC cells and specifically triggered TNBC cell lysis in vitro. Additionally, the CAR-T cells inhibited growth of cell-line- and patient-derived xenograft TNBC tumors in mice. These results suggest that EGFR-specific CAR-T cells might be a promising therapeutic strategy in patients with high-EGFR-expressing TNBC.

    EGFR expression in breast cancer cell lines. EGFR expression in TNBC cell lines (HS578T, MDA-MB-468, and MDA-MB-231) and MCF-7 cells detected by (A) real-time RT PCR, (B) Western blot, and (C) flow cytometry. Error bars represent means ± SEM. T-tests were used for statistical analysis; ***p < 0.001.



    Characterization of T lymphocytes from PBMCs. (A–B) T cell phenotypes and subsets were examined by flow cytometry after labeling with anti-CD3-PE-Cy7, anti-CD4-PE, and anti-CD8-APC-Cy7.



    Generation, isolation, and characterization of EGFR-specific CAR T lymphocytes. (A) Schematic illustration of Con-CAR, EGFR-CAR-1, and EGFR-CAR-2. (B) Expression of exogenous CD3ζin non-transduced T cells, con-CAR T cells, EGFR-CAR-1 T cells, and EGFR-CAR-2 T cells was measured using Western blots; β-actin was used as an endogenous control. (C) GFP and EGFR-GFP antigens were detected by Western blot. (D) Transduced T cells were stained with GFP and EGFR-GFP antigen and then detected by flow cytometry.



    Cytokine release and cytotoxicity assay. Cytokine release in target cells in response to effector non-transduced T cells, con-CAR-T cells, EGFR-CAR-1 T cells, and EGFR-CAR-2 T cells. Effector cells were co-cultured with target cells (HS578T, MDA-MB-468, MDA-MB-231, and MCF-7) at an E:T ratio of 10:1 for 24h. (A) IFN-γ, (B) IL-4, and (C) IL-2 levels were assayed in the co-culture supernatants. Cytotoxicity was measured in each group using a standard LDH release assay. Effector cells were co-cultured with (D) HS578T, (E) MDA-MB-468, (F) MDA-MB-231, and (G) MCF-7 target cells at E:T ratios of 5:1, 10:1, or 20:1 for 24h.



    TNBC cell lysis assay. (A) HS578T, (B) MDA-MB-468, and (C) MDA-MB-231 cells were labeled with YOYO-3 (red). Non-transduced T cells, con-CAR-T cells, EGFR-CAR-1 T cells, and EGFR-CAR-2 T effector cells were co-cultured with target cells at an E:T ratio of 10:1 for 24h.



    EGFR-specific CAR-T cells inhibited EGFR-expressing TNBC tumor growth in CLDX mouse model. Compared to con-CAR-T cells, EGFR-CAR-1 and EGFR-CAR-2 T cells decreased the weights and volumes of tumors induced by (A, B) HS578, (D, E) MDA-MB-468, and (G, H) MDA-MB-231 TNBC cells, but did not affect body weight (C, F, I). Error bars represent means ± SEM. T-tests were used for statistical analysis; *p < 0.05, ** p < 0.01, ***p < 0.001.



    EGFR-CAR-T cells inhibited high-EGFR-expressing TNBC tumor growth in PDX mouse model. ER, PR, HER2, and EGFR expression in (A) clinical breast cancer samples and (B) breast cancer tumors in PDX mice were assessed in immunohistochemical assays. Compared to con-CAR-T cells, EGFR-CAR-1 and EGFR-CAR-2 T cells decreased breast cancer (C) tumor weights and (D) tumor volumes but did not affect (E) body weights. Error bars represent means ± SEM. T-tests were used for statistical analysis; *p < 0.05, **p < 0.01.



  • Research Paper Volume 11, Issue 16 pp 6286-6311

    Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis

    Relevance score: 14.071408
    Yunhai Li, Dejuan Yang, Ping Chen, Xuedong Yin, Jiazheng Sun, Hongzhong Li, Guosheng Ren
    Keywords: network meta-analysis, triple-negative breast cancer, neoadjuvant chemotherapy, pathological complete response
    Published in Aging on August 24, 2019
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    Different neoadjuvant chemotherapies are available for triple-negative breast cancer (TNBC). Here, we performed a network meta-analysis to evaluate the pathological complete response (pCR) benefit and safety of treatment regimens. Pairwise and Bayesian network meta-analyses were performed to compare direct and indirect evidence, respectively. Twenty-three studies involving 12 regimens namely standard chemotherapeutic agents, bevacizumab (B)-, platinum salts (P)-, B plus P (BP)-, poly(ADP-ribose) polymerase inhibitors (Pi)-, P plus Pi (PPi)-, capecitabine (Ca)-, gemcitabine (Ge)-, zoledronic acid (Za)-, everolimus (E)-, P plus E (PE)-, and gefitinib (G)-containing regimens. The results showed that P-, B-, PPi-, and Za-containing regimens achieved higher pCR than standard chemotherapeutic agents. BP-containing regimens had a better pCR than B-containing regimens. In indirect comparisons, Za-, BP-, P-, and B-containing regimens were the top four strategies with the highest probability for pCR. Benefit-risk analysis showed that B-containing regimens had the highest acceptability of being the best treatment for better pCR achievement with fewer SAEs. The addition of P, B, BP, PPi, and Za to standard chemotherapeutic agents enhanced the pCR, but a balance between efficacy and safety should be carefully considered. B-containing regimens might be the best choice for neoadjuvant chemotherapy due to its better efficacy and tolerability.

    A PRISMA flow chart of the literature search and study selection in this meta-analysis.



    Network diagram of eligible comparisons included in the network meta-analysis for pathological complete response (pCR). The node size is proportional to the total number of patients in the regimen. The width of each line is proportional to the number of studies comparing the two regimens linked by the line.



    Forest plots of pair-wise meta-analyses for pathological complete response (pCR). (A) Standard chemotherapeutic agents vs. P-containing regimens. (B) Standard chemotherapeutic agents vs. B-containing regimens. (C) B-containing regimens vs. BP-containing regimens. (D) Standard chemotherapeutic agents vs. PPi-containing regimens. (E) Standard chemotherapeutic agents vs. Ca-containing regimens. (F) Standard chemotherapeutic agents vs. Za-containing regimens.



    Bayesian network meta-analysis for pathological complete response (pCR). (A) The league table of comparisons. Data are presented as odds radio (OR) and 95% confidence intervals (CI). An OR>1 favors the column-defining treatment, and an OR<1 favors the row-defining treatment. (B) Heatmap of the rank probability of the twelve regimens for pCR. Rank 1 represents the best treatment and rank 12 represents the worst. Rank probabilities sum to one, both within a rank over treatments and within a treatment over ranks.



    Bayesian network meta-analysis for grade 3–4 hematological adverse events. (A) The league table for comparisons of anemia. (B) The league table for comparisons of neutropenia. (C) The league table for comparisons of thrombocytopenia. Data are presented as odds radio (OR) and 95% confidence intervals (CI). An OR>1 favors the row-defining treatment, and OR<1 favors the column-defining treatment.



    Stochastic multi-criteria acceptability analysis for benefit-risk. (A) Rank probability of regimens based on synthesizing pCR and anemia. (B) Rank probability of regimens based on synthesizing pCR and neutropenia. (C) Rank probability of regimens based on synthesizing pCR and thrombocytopenia. (D) Rank probability of regimens based on synthesizing pCR and the three serious adverse events. Rank 1 represents the best treatment and rank N represents the worst. The proportion corresponds to the probability of each regimen to be at a specific rank.



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