@article{88311,
  keywords = {Animals, Humans, signal transduction, Cell Proliferation, Blotting, Western, Mice, Female, Cell Line, Tumor, Cell Movement, Breast Neoplasms, Antibodies, Monoclonal, Antineoplastic Agents, Reverse Transcriptase Polymerase Chain Reaction, Transforming Growth Factor beta, Neoplasm Metastasis, Mice, Nude, Neovascularization, Pathologic, Xenograft Model Antitumor Assays, Pyrazoles, Pyrroles},
  author = {Vidya Ganapathy and Rongrong Ge and Alison Grazioli and Wen Xie and Whitney Banach-Petrosky and Yibin Kang and Scott Lonning and John McPherson and Jonathan Yingling and Swati Biswas and Gregory Mundy and Michael Reiss},
  title = {Targeting the Transforming Growth Factor-beta pathway inhibits human basal-like breast cancer metastasis.},
  abstract = {<p>BACKGROUND: Transforming Growth Factor beta (TGF-beta) plays an important role in tumor invasion and metastasis. We set out to investigate the possible clinical utility of TGF-beta antagonists in a human metastatic basal-like breast cancer model. We examined the effects of two types of the TGF-beta pathway antagonists (1D11, a mouse monoclonal pan-TGF-beta neutralizing antibody and LY2109761, a chemical inhibitor of TGF-beta 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-beta-induced phosphorylation of receptor-associated Smads in all MDA-MB-231 subclones in vitro. Moreover, both antagonists inhibited TGF-beta stimulated in vitro migration and invasiveness of MDA-MB-231 subclones, indicating that these processes are partly driven by TGF-beta. 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-beta 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-beta plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-beta signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-beta pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer. CONCLUSIONS: In aggregate, these studies support the notion that TGF-beta plays an important role in both bone-and lung metastases of basal-like breast cancer, and that inhibiting TGF-beta signaling results in a therapeutic effect independently of the tissue-tropism of the metastatic cells. Targeting the TGF-beta pathway holds promise as a novel therapeutic approach for metastatic basal-like breast cancer.</p>
},
  year = {2010},
  journal = {Mol Cancer},
  volume = {9},
  pages = {122},
  month = {05/2010},
  issn = {1476-4598},
  doi = {10.1186/1476-4598-9-122},
  language = {eng},
}