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

J Clin Invest. 2014 Apr;124(4):1646-59. doi: 10.1172/JCI71812. Epub 2014 Mar 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / prevention & control
  • Bone Neoplasms / secondary*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Female
  • GTPase-Activating Proteins / antagonists & inhibitors
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Parathyroid Hormone-Related Protein / antagonists & inhibitors*
  • Parathyroid Hormone-Related Protein / genetics
  • Parathyroid Hormone-Related Protein / metabolism
  • Signal Transduction
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tumor Microenvironment
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • rho GTP-Binding Proteins / metabolism

Substances

  • DLC-1 (deleted in liver cancer) protein, mouse
  • DLC1 protein, human
  • GTPase-Activating Proteins
  • PTHLH protein, human
  • Parathyroid Hormone-Related Protein
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Tumor Suppressor Proteins
  • rho GTP-Binding Proteins