DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis
Yufeng Wang, … , Qifeng Yang, Guohong Hu
Yufeng Wang, … , Qifeng Yang, Guohong Hu
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(4):1646-1659. https://doi.org/10.1172/JCI71812.
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Research Article Oncology

DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

Abstract

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.

Authors

Yufeng Wang, Rong Lei, Xueqian Zhuang, Ning Zhang, Hong Pan, Gang Li, Jing Hu, Xiaoqi Pan, Qian Tao, Da Fu, Jianru Xiao, Y. Eugene Chin, Yibin Kang, Qifeng Yang, Guohong Hu

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Figure 3

DLC1-Rho signaling regulates osteoclast maturation in the bone microenvironment.

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DLC1-Rho signaling regulates osteoclast maturation in the bone microenvi...
(A) Osteoclastogenesis assays of primary bone marrow cultured together with DLC1 KD or control cells treated with TGF-β, or in CM from SCP28 cells treated with TGF-β, C3, and/or Y27632 (n = 3). (B) Osteoclastogenesis assays of primary bone marrow culture in SCP2 CM (n = 3). Representative TRAP staining images are also shown. Arrows denote TRAP-positive osteoclasts. (C) Osteoclastogenesis assays of CM from additional MDA231 derivative cell lines (n = 3). Green and red text denotes cell lines with high and low DLC1 expression, respectively. (D) Osteoclastogenesis assays of CM from cancer cells treated with various genes or chemical reagents (n = 3). (E) TRAP staining of bone metastasis tumors from animals injected with DLC1 KD or OE cancer cells. (F) Osteoclast cells along the tumor-bone interface (n = 3). Scale bars: 100 μm. *P < 0.05, **P < 0.01.