TGF-? Stimulation of EMT Programs Elicits Non-genomic ER-? Activity and Anti-estrogen Resistance in Breast Cancer Cells.

ABSTRACT: Estrogen receptor-? (ER-?) activation drives the progression of luminal breast cancers. Signaling by transforming growth factor-? (TGF-?) typically opposes the actions of ER-?; it also induces epithelial-mesenchymal transition (EMT) programs that promote breast cancer dissemination, stemness, and chemoresistance. The impact of EMT programs on nongenomic ER-? signaling remains unknown and was studied herein.MCF-7 and BT474 cells were stimulated with TGF-? to induce EMT programs, at which point ER-? expression, localization, and nongenomic interactions with receptor tyrosine kinases and MAP kinases (MAPKs) were determined. Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated.TGF-? stimulated MCF-7 and BT474 cells to acquire EMT phenotypes, which enhanced cytoplasmic accumulation of ER-? without altering its expression. Post-EMT cells exhibited (i) elevated expression of EGFR and IGF1R, which together with Src formed cytoplasmic complexes with ER-?; (ii) enhanced coupling of EGF, IGF-1 and estrogen to the activation of MAPKs; and (iii) reduced sensitivity to tamoxifen, an event reversed by administration of small molecule inhibitors against the receptors for TGF-?, EGF, and IGF-1, as well as those against MAPKs.EMT stimulated by TGF-? promotes anti-estrogen resistance by activating EGFR-, IGF1R-, and MAPK-dependent nongenomic ER-? signaling.

SUBMITTER: Tian M 

PROVIDER: S-EPMC5612668 | biostudies-other | 2017

REPOSITORIES: biostudies-other