Noncanonical TGF-β Signaling During Mammary Tumorigenesis

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

Abstract

Breast cancer is a heterogeneous disease comprised of at least five major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United States. Although metastasis clearly represents the most lethal characteristic of breast cancer, our understanding of the molecular mechanisms that govern this event remains inadequate. Clinically, ~30% of breast cancer patients diagnosed with early-stage disease undergo metastatic progression, an event that (a) severely limits treatment options, (b) typically results in chemoresistance and low response rates, and (c) greatly contributes to aggressive relapses and dismal survival rates. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates all phases of postnatal mammary gland development, including branching morphogenesis, lactation, and involution. TGF-β also plays a prominent role in suppressing mammary tumorigenesis by preventing mammary epithelial cell (MEC) proliferation, or by inducing MEC apoptosis. Genetic and epigenetic events that transpire during mammary tumorigenesis conspire to circumvent the tumor suppressing activities of TGF-β, thereby permitting late-stage breast cancer cells to acquire invasive and metastatic phenotypes in response to TGF-β. Metastatic progression stimulated by TGF-β also relies on its ability to induce epithelial-mesenchymal transition (EMT) and the expansion of chemoresistant breast cancer stem cells. Precisely how this metamorphosis in TGF-β function comes about remains incompletely understood; however, recent findings indicate that the initiation of oncogenic TGF-β activity is contingent upon imbalances between its canonical and noncanonical signaling systems. Here we review the molecular and cellular contributions of noncanonical TGF-β effectors to mammary tumorigenesis and metastatic progression.

Keywords

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

Abbreviations

AKT/PKB

protein kinase B

BMDC

bone marrow-derived cell

CSC

cancer stem cell

ECM

extracellular matrix

EGF

epidermal growth factor

EMT

epithelial-mesenchymal transition

ERK

extracellular signal-regulated kinase

FAK

focal adhesion kinase

HGF

hepatocyte growth factor

hnRNP E1

heterogeneous nuclear ribronucleoprotein E1

ILEI

interleukin-like EMT inducer

JNK

c-Jun N-terminal kinase

MAP kinase

mitogen-activated protein kinase

MEC

mammary epithelial cell

MET

mesenchymal-epithelial transition

miR

microRNA

MMP

matrix metalloproteinase

MSP

macrophage-stimulating protein

MTA3

metastasis associated protein 3

mTOR

mammalian target of rapamycin

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

TRAF6

TNF receptor-associated factor 6

uPA

urokinase plasminogen activator

uPAR

uPA receptor

ZO-1

zonula occluden-1

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jenny G. Parvani
    • 1
  • Molly A. Taylor
    • 1
  • William P. Schiemann
    • 2
  1. 1.Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandUSA
  2. 2.Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandUSA

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