Inhibition of BMP signaling suppresses metastasis in mammary cancer

Oncogene. 2015 May 7;34(19):2437-49. doi: 10.1038/onc.2014.189. Epub 2014 Jul 7.

Abstract

Bone morphogenetic proteins (BMPs) are secreted cytokines/growth factors that have differing roles in cancer. BMPs are overexpressed in human breast cancers, but loss of BMP signaling in mammary carcinomas can accelerate metastasis. We show that human breast cancers display active BMP signaling, which is rarely downregulated or homozygously deleted. We hypothesized that systemic inhibition of BMP signaling in both the tumor and the surrounding microenvironment could prevent tumor progression and metastasis. To test this hypothesis, we used DMH1, a BMP antagonist, in MMTV.PyVmT expressing mice. Treatment with DMH1 reduced lung metastasis and the tumors were less proliferative and more apoptotic. In the surrounding tumor microenvironment, treatment with DMH1 altered fibroblasts, lymphatic vessels and macrophages to be less tumor promoting. These results indicate that inhibition of BMP signaling may successfully target both the tumor and the surrounding microenvironment to reduce tumor burden and metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism
  • Female
  • Fibroblasts / drug effects
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / prevention & control*
  • Lung Neoplasms / secondary
  • Lymphatic Vessels / drug effects
  • Lymphatic Vessels / metabolism
  • Macrophages / drug effects
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pyrazoles / pharmacology*
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects*

Substances

  • Bone Morphogenetic Proteins
  • DMH1 compound
  • Pyrazoles
  • Quinolines