Research Paper Volume 9, Issue 2 pp 508—523

Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor

Figure 6. Proposed resveratrol’s mechanism of action in a luminal B breast cancer model. Our data show that resveratrol down-regulates ERα and lowers the chymotrypsin-like activity of the 20S proteasome in HER2+/ERα+ breast cancer, leading to an increased accumulation of Δ16HER2, which efficiently couples to HER3 and activates the PI3K-AKT-mTOR pathway. In particular, Δ16HER2/HER3 heterodimers trigger the mTORC1/p70S6K/4EBP1 signaling axis inducing an up-regulation of protein synthesis and cell growth. On the other hand, resveratrol inhibits mTORC2 and promotes phosphorylation of PTEN, reducing its catalytic activity, thereby enhancing PI3K-mediated AKT activation, while feedback loops compensate it.