Breast Cancer Research and Treatment

, Volume 115, Issue 3, pp 453–495 | Cite as

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

  • Antoinette R. Tan
  • Gabriela Alexe
  • Michael ReissEmail author


In most human breast cancers, lowering of TGFβ receptor- or Smad gene expression combined with increased levels of TGFβs in the tumor microenvironment is sufficient to abrogate TGFβs tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFβ signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFβ tumor suppression. In mouse models of “triple-negative” or basal-like breast cancer, treatment with TGFβ neutralizing antibodies or receptor kinase inhibitors strongly inhibits development of lung- and bone metastases. These TGFβ antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFβ target genes upregulation in human breast cancers suggest that TGFβ may drive tumor progression in estrogen-independent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFβ appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptor-positive, luminal cells are unresponsive to TGFβ because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFβ, while antiestrogens act by upregulating TGFβ. This model predicts that inhibiting TGFβ signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFβ antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These predictions need to be addressed prospectively in clinical trials and should inform the selection of patient populations most likely to benefit from this novel anti-metastatic therapeutic approach.


Breast cancer Transforming growth factor-β Metastasis Antibody Receptor kinase inhibitor Cancer stem cells 





Ataxia teleangiectasia mutated protein


Cancer initiating cells


Dendritic cells




Dominant negative TGFβ type II receptor


Epithelial to mesenchymal transition


Estrogen receptor


Expressed sequence tag


Fc-soluble TGFβ type II receptor fusion protein


Human mammary epithelial cells




Mouse mammary tumor virus


Natural killer cells


Peripheral blood mononuclear cells


Progesterone receptor


Polyoma virus middle T antigen


TGFβ response gene signature


TGFβ type I receptor gene


TGFβ type II receptor gene


Transforming growth factor-α


Transforming growth factor-β




TGFβ receptor


Whey acidic protein



This work was supported by Public Health Service Awards CA-41556, CA-120623 and CA-129125 to MR from the National Cancer Institute, as well as by the Cancer Center Support Grant CA-72720 from the National Cancer Institute.


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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Antoinette R. Tan
    • 1
  • Gabriela Alexe
    • 2
  • Michael Reiss
    • 1
    • 3
    Email author
  1. 1.Division of Medical Oncology, Department of Internal MedicineUMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New JerseyNew BrunswickUSA
  2. 2.Department of Human Genetics and Clinical BiomarkersBristol-Myers SquibbPrincetonUSA
  3. 3.Department of Molecular Genetics, Microbiology & ImmunologyUMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New JerseyNew BrunswickUSA

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