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The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells

  • Molly A. Taylor
  • Jenny G. Parvani
  • William P. Schiemann
Article

Abstract

Epithelial-mesenchymal transition (EMT) is an essential process that drives polarized, immotile mammary epithelial cells (MECs) to acquire apolar, highly migratory fibroblastoid-like features. EMT is an indispensable process that is associated with normal tissue development and organogenesis, as well as with tissue remodeling and wound healing. In stark contrast, inappropriate reactivation of EMT readily contributes to the development of a variety of human pathologies, particularly those associated with tissue fibrosis and cancer cell invasion and metastasis, including that by breast cancer cells. Although metastasis is unequivocally the most lethal aspect of breast cancer and the most prominent feature associated with disease recurrence, the molecular mechanisms whereby EMT mediates the initiation and resolution of breast cancer metastasis remains poorly understood. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is intimately involved in regulating numerous physiological processes, including cellular differentiation, homeostasis, and EMT. In addition, TGF-β also functions as a powerful tumor suppressor in MECs, whose neoplastic development ultimately converts TGF-β into an oncogenic cytokine in aggressive late-stage mammary tumors. Recent findings have implicated the process of EMT in mediating the functional conversion of TGF-β during breast cancer progression, suggesting that the chemotherapeutic targeting of EMT induced by TGF-β may offer new inroads in ameliorating metastatic disease in breast cancer patients. Here we review the molecular, cellular, and microenvironmental factors that contribute to the pathophysiological activities of TGF-β during its regulation of EMT in normal and malignant MECs.

Keywords

Epithelial-mesenchymal Transition Metastasis Signal transduction Transforming growth factor-β Tumor microenvironment 

Abbreviations

α-SMA

α-smooth muscle actin

BMP

Bone morphogenic protein

ECM

Extracellular matrix

EGF

Epidermal growth factor

EMT

Epithelial-mesenchymal transition

ERK

Extracellular signal-regulated kinase

FAK

Focal adhesion kinase

JNK

c-Jun N-terminal kinase

MAP kinase

Mitogen-activated protein kinase

MEC

Mammary epithelial cell

mTOR

Mammalian target of rapamycin

MET

Mesenchymal-epithelial transition

MTA3

Metastasis associated protein 3

NF-κB

Nuclear factor-κB

PAI

Plasminogen activator inhibitor

PDGF

Platelet-derived growth factor

PI3K

Phosphoinositide-3-kinase

TβR-I

TGF-β type I receptor

TβR-II

TGF-β type II receptor

TβR-III

TGF-β type III receptor

TGF-β

Transforming growth factor-β

uPA

Urokinase plasminogen activator

uPAR

uPA receptor

ZO-1

Zonula occluden-1

Notes

Acknowledgements

We thank members of the Schiemann Laboratory for critical comments and reading of the manuscript. W.P.S. was supported by grants from the National Institutes of Health (CA114039 and CA129359), the Komen Foundation (BCTR0706967), and the Department of Defense (BC084651), while M.A.T. was supported by the Department of Defense (BC093128).

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Molly A. Taylor
    • 1
  • Jenny G. Parvani
    • 1
  • William P. Schiemann
    • 1
  1. 1.Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandUSA

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