Background: Flavin containing dimethylaniline monoxygenase 2 (FMO2), is downexpressed in diverse tumors and displays vital roles in tumorigenesis. However, the prognostic value and potential mechanism of FMO2 in breast cancer remain unclear.

Methods: The expression of FMO2 was analyzed and the relationship between FMO2 expression level and clinical indicators in breast cancer was analyzed. Then the prognostic value of FMO2 in breast cancer was assessed. The FMO2-correlated genes were obtained, and the highest-ranked gene was chosen. The expression, therapeutic responder analysis, and gene set enrichment analysis of the highest-ranked gene were conducted.

Results: FMO2 was downregulated in breast cancer and was closely related to clinical indicators. Patients with decreased FMO2 expression showed poor overall survival, post-progression survival, relapse-free survival, and distant metastasis-free survival. FMO2 correlates with N/ER/PR subgroups in breast cancer and patients with high FMO2 levels were sensitive to anti-programmed cell death protein 1, anti-programmed death-ligand 1, and anti-cytotoxic T-lymphocyte antigen 4 immunotherapies. Mechanically, FMO2 was positively and highly correlated with secreted Frizzled-related protein 1 (SFRP1), which was downregulated in breast cancer due to hypermethylation. Moreover, SFRP1 was correlated to pathological complete response and relapse-free survival status at 5 years regardless of any chemotherapy, hormone therapy, and anti-HER2 therapy. Gene set enrichment analysis revealed enrichment of component and coagulation cascades, focal adhesion, protein export, and spliceosome.

Conclusions: FMO2 was lower expressed in breast cancer than normal tissues and contributes to subtype classification and prognosis prediction with co-expressed SFRP1.