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

Vidya Ganapathy1, Rongrong Ge1, Alison Grazioli1, Wen Xie1, Whitney Banach-Petrosky1, Yibin Kang2, Scott Lonning3, John McPherson3, Jonathan M Yingling4, Swati Biswas5, Gregory R Mundy5 and Michael Reiss1*

Author Affiliations

1 Division of Medical Oncology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, New Brunswick, NJ, USA

2 Department of Molecular Biology, Princeton University, Princeton, NJ, USA

3 Genzyme Corporation, Framingham, MA, USA

4 Lilly Research Laboratories, Indianapolis, IN, USA

5 Dept. of Cancer Biology, Vanderbilt Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

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Molecular Cancer 2010, 9:122  doi:10.1186/1476-4598-9-122

Published: 26 May 2010

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.