Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis

Vidya Ganapathy, Rongrong Ge, Alison Grazioli, Wen Xie, Whitney Banach-Petrosky, Yibin Kang, Scott Lonning, John McPherson, Jonathan M. Yingling, Swati Biswas, Gregory R. Mundy, Michael Reiss

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117 Scopus citations

Abstract

Background: Transforming Growth Factor β (TGF-β) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-β antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-β pathway antagonists (1D11, a mouse monoclonal pan-TGF-β neutralizing antibody and LY2109761, a chemical inhibitor of TGF-β type I and II receptor kinases) on sublines of basal cell-like MDA-MB-231 human breast carcinoma cells that preferentially metastasize to lungs (4175TR, 4173) or bones (SCP2TR, SCP25TR, 2860TR, 3847TR).Results: Both 1D11 and LY2109761 effectively blocked TGF-β-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-β stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-β. In addition, both antagonists significantly reduced the metastatic burden to either lungs or bones in vivo, seemingly independently of intrinsic differences between the individual tumor cell clones. Besides inhibiting metastasis in a tumor cell autonomous manner, the TGF-β antagonists inhibited angiogenesis associated with lung metastases and osteoclast number and activity associated with lytic bone metastases. In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.Conclusions: In aggregate, these studies support the notion that TGF-β plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-β signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-β pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.

Original languageEnglish (US)
Article number122
JournalMolecular Cancer
Volume9
DOIs
StatePublished - May 26 2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research

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    Ganapathy, V., Ge, R., Grazioli, A., Xie, W., Banach-Petrosky, W., Kang, Y., Lonning, S., McPherson, J., Yingling, J. M., Biswas, S., Mundy, G. R., & Reiss, M. (2010). Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis. Molecular Cancer, 9, [122]. https://doi.org/10.1186/1476-4598-9-122