@article{88081,
  keywords = {Animals, Humans, signal transduction, Mice, Female, Cell Line, Tumor, Breast Neoplasms, rho GTP-Binding Proteins, Transforming Growth Factor beta, Gene Knockdown Techniques, Tumor Suppressor Proteins, Mice, Inbred BALB C, GTPase-Activating Proteins, Osteoclasts, Tumor Microenvironment, Bone Neoplasms, Mammary Neoplasms, Experimental, Parathyroid Hormone-Related Protein, Smad3 Protein},
  author = {Yufeng Wang and Rong Lei and Xueqian Zhuang and Ning Zhang and Hong Pan and Gang Li and Jing Hu and Xiaoqi Pan and Qian Tao and Da Fu and Jianru Xiao and Eugene Chin and Yibin Kang and Qifeng Yang and Guohong Hu},
  title = {DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.},
  abstract = {<p>Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.</p>
},
  year = {2014},
  journal = {J Clin Invest},
  volume = {124},
  pages = {1646-59},
  month = {04/2014},
  issn = {1558-8238},
  doi = {10.1172/JCI71812},
  language = {eng},
}