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Noncanonical TGF-β Signaling During Mammary Tumorigenesis

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

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.

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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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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 (CA129359), the Komen Foundation (BCTR0706967), and the Department of Defense (BC084651), while M.A.T. was supported by the Department of Defense (BC093128).

Financial Support

W.P.S. was supported by grants from the National Institutes of Health (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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Authors and Affiliations

  1. Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research Building, Room 2404, 2103 Cornell Road, Cleveland, OH, 44106, USA

    Jenny G. Parvani & Molly A. Taylor

  2. Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research Building, Room 2131, 2103 Cornell Road, Cleveland, OH, 44106, USA

    William P. Schiemann

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  1. Jenny G. Parvani
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  2. Molly A. Taylor
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Correspondence to William P. Schiemann.

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Jenny G. Parvani and Molly A. Taylor were equal contributors to this work.

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Parvani, J.G., Taylor, M.A. & Schiemann, W.P. Noncanonical TGF-β Signaling During Mammary Tumorigenesis. J Mammary Gland Biol Neoplasia 16, 127–146 (2011). https://doi.org/10.1007/s10911-011-9207-3

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