title: 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.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Lei
authors.forename: Xueqian
authors.initials: X
authors.lastname: Zhuang
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Pan
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
authors.forename: Da
authors.initials: D
authors.lastname: Fu
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C430864:DLC-1 (deleted in liver cancer) protein, mouse; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins