Noncanonical TGF-β Signaling During Mammary Tumorigenesis

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


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.


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



protein kinase B


bone marrow-derived cell


cancer stem cell


extracellular matrix


epidermal growth factor


epithelial-mesenchymal transition


extracellular signal-regulated kinase


focal adhesion kinase


hepatocyte growth factor

hnRNP E1

heterogeneous nuclear ribronucleoprotein E1


interleukin-like EMT inducer


c-Jun N-terminal kinase

MAP kinase

mitogen-activated protein kinase


mammary epithelial cell


mesenchymal-epithelial transition




matrix metalloproteinase


macrophage-stimulating protein


metastasis associated protein 3


mammalian target of rapamycin


nuclear factor-κB


plasminogen activator inhibitor


platelet-derived growth factor




TGF-β type I receptor


TGF-β type II receptor


TGF-β type III receptor


transforming growth factor-β


TNF receptor-associated factor 6


urokinase plasminogen activator


uPA receptor


zonula occluden-1



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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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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