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Tian et al. J Cancer Metastasis Treat 2017;3:150-60 Journal of
DOI: 10.20517/2394-4722.2017.38
Cancer Metastasis and Treatment

www.jcmtjournal.com
Original Article Open Access

TGF-β stimulation of EMT programs elicits

non-genomic ER-α activity and anti-estrogen

resistance in breast cancer cells

Maozhen Tian, William P. Schiemann

Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.

Correspondence to: Dr. William P. Schiemann, Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research
Building, 2103 Cornell Road, Cleveland, OH 44106, USA. E-mail: william.schiemann@case.edu
How to cite this article: Tian M, Schiemann WP. TGF-β stimulation of EMT programs elicits non-genomic ER-α activity and anti-estrogen
resistance in breast cancer cells. J Cancer Metastasis Treat 2017;3:150-60.
ABSTRACT
Article history: Aim: Estrogen receptor-α (ER-α) activation drives the progression of luminal breast
Received: 02-06-2017 cancers. Signaling by transforming growth factor-β (TGF-β) typically opposes the actions
Accepted: 12-08-2017 of ER-α; it also induces epithelial-mesenchymal transition (EMT) programs that promote
Published: 21-08-2017 breast cancer dissemination, stemness and chemoresistance. The impact of EMT programs
on nongenomic ER-α signaling remains unknown and was studied herein. Methods:
Key words: MCF-7 and BT474 cells were stimulated with TGF-β to induce EMT programs, at which
Breast cancer, point ER-α expression, localization, and nongenomic interactions with receptor tyrosine
epithelial-mesenchymal kinases and MAP kinases (MAPKs) were determined. Cell sensitivity to anti-estrogens
transition, both before and after traversing the EMT program was also investigated. Results: TGF-
estrogen receptor-α, β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes, which enhanced
growth factor, cytoplasmic accumulation of ER-α without altering its expression. Post-EMT cells
signal transduction, exhibited: (1) elevated expression of EGFR and IGF1R, which together with Src formed
tamoxifen resistance, cytoplasmic complexes with ER-α; (2) enhanced coupling of EGF, IGF-1 and estrogen
transforming growth factor-β 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.

INTRODUCTION and by creating a cell microenvironment that inhibits
cell motility, invasion and metastasis. However, during
Transforming growth factor-β (TGF-β) normally breast cancer development, the tumor suppressing
acts as a suppressor of mammary tumorigenesis by functions of TGF-β is frequently subverted, thus
inducing cellular arrest, apoptosis, or differentiation, converting TGF-β from a tumor suppressor to a

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