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 Reiss
Review

Abstract

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.

Keywords

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

Abbreviations

4-OH-T

4-Hydroxy-tamoxifen

ATM

Ataxia teleangiectasia mutated protein

CIC

Cancer initiating cells

DC

Dendritic cells

DMBA

7,12-Dimethylbenz[α]anthracene

DNTβRII

Dominant negative TGFβ type II receptor

EMT

Epithelial to mesenchymal transition

ER

Estrogen receptor

EST

Expressed sequence tag

Fc:TβRII

Fc-soluble TGFβ type II receptor fusion protein

HMEC

Human mammary epithelial cells

IHC

Immunohistochemistry

MMTV

Mouse mammary tumor virus

NK

Natural killer cells

PBMC

Peripheral blood mononuclear cells

PR

Progesterone receptor

PyVmT

Polyoma virus middle T antigen

TBRS

TGFβ response gene signature

TGFBR1

TGFβ type I receptor gene

TGFBR2

TGFβ type II receptor gene

TGFα

Transforming growth factor-α

TGFβ

Transforming growth factor-β

TPA

12-Tetradecanoyl-phorbol-13-acetate

TβR

TGFβ receptor

WAP

Whey acidic protein

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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
  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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