TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen resistance in breast cancer cells

Abstract

Aim: Estrogen receptor-α (ER-α) activation drives the progression of luminal breast cancers. Signaling by transforming growth factor-β (TGF-β) typically opposes the actions of ER-α; it also induces epithelial-mesenchymal transition (EMT) programs that promote breast cancer dissemination, stemness and chemoresistance. The impact of EMT programs on nongenomic ER-α signaling remains unknown and was studied herein.

Methods: MCF-7 and BT474 cells were stimulated with TGF-β to induce EMT programs, at which point ER-α 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.

Results: TGF-β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes, which enhanced cytoplasmic accumulation of ER-α without altering its expression. Post-EMT cells exhibited: (1) elevated expression of EGFR and IGF1R, which together with Src formed cytoplasmic complexes with ER-α; (2) enhanced coupling of EGF, IGF-1 and estrogen to the activation of MAPKs; and (3) reduced sensitivity to tamoxifen, an event reversed by administration of small molecule inhibitors against the receptors for TGF-β, EGF, and IGF-1, as well as those against MAPKs.

Conclusion: EMT stimulated by TGF-β promotes anti-estrogen resistance by activating EGFR-, IGF1R-, and MAPK-dependent nongenomic ER-α signaling.

Keywords

Breast cancer / epithelial-mesenchymal transition / estrogen receptor-α / growth factor / signal transduction / tamoxifen resistance / transforming growth factor-β

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