Bisphenol A-mediated GPER1/PPARγ/ACC/FAS signaling induces de novo lipogenesis and lipid accumulation in luminal and triple-negative breast cancer cells to regulate epithelial-mesenchymal plasticity.

Enhanced de novo lipogenesis (DNL) is a hallmark of metastatic breast cancer (BC). Environmental exposure to endocrine-disrupting chemicals (EDCs), including bisphenols (such as BPA), is strongly linked to altered lipid metabolism and breast cancer. However, the linkage between EDC-mediated DNL and metastatic transformation in BC remains poorly understood. Here, we demonstrate that long-term exposure to BPA stimulates DNL in both estrogen-sensitive (MCF-7) and triple-negative breast cancer (TNBC) cells (MDA-MB-231) by activating PPARγ/ACC/FAS-driven lipogenic signaling. Moreover, this signalling regulates the migratory and invasive abilities of both BC cell types by inducing epithelial-mesenchymal transition (EMT). Pharmacological inhibition of PPARγ suppressed BPA-induced DNL, vis-à-vis EMT, in both BC cells. Furthermore, BPA-induced GPER1, a membrane-bound estrogen receptor (ER), was found to regulate PPARγ/ACC/FAS-mediated lipogenic signaling, subsequently affecting DNL and EMT in BC cells. Pharmacological inhibition or transient siRNA-mediated knockdown of GPER1 prevented BPA-induced PPARγ/ACC/FAS-driven DNL and EMT in both BC cell lines. Overall, we provide a novel mechanistic link between EDCs and DNL that promotes BC metastasis via GPER1-dependent activation of lipogenic PPARγ/ACC/FAS signaling in both TNBC and ERα-positive BC cells. Hence, GPER1 may act as a signalling hub to mediate EDC-associated DNL-like modifications in BC cells, thereby fueling epithelial-mesenchymal plasticity.