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

The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-inducible in vivo models. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Delta 16HER2 mice as HER2+/ER alpha+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4 mu g/mouse) shortened tumor latency and enhanced tumor multiplicity in Delta 16HER2 mice. This in vivo tumor-promoting effect of resveratrol was associated with up-regulation of Delta 16HER2 and down-regulation of ER alpha protein levels and was recapitulated in vitro by murine (CAM6) and human (BT474) tumor cell lines. Our results demonstrate that resveratrol, acting as a proteasome inhibitor, leads to Delta 16HER2 accumulation which favors the formation of Delta 16HER2/HER3 heterodimers. The consequential activation of downstream mTORC1/p70S6K/4EBP1 pathway triggers cancer growth and proliferation. This study provides evidence that resveratrol mechanism of action (and hence its effects) depends on the intrinsic molecular properties of the cancer model under investigation, exerting a tumor-promoting effect in luminal B breast cancer subtype models.