Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice

J Clin Invest. 2010 Jul;120(7):2319-30. doi: 10.1172/JCI38291. Epub 2010 Jun 23.

Abstract

Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERalpha, direct ERalpha-Galphai interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERalpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cell Proliferation
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / metabolism
  • Enzyme Activation / genetics
  • Estradiol / genetics
  • Estradiol / metabolism
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogens / genetics
  • Estrogens / metabolism
  • Female
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Mice, Nude
  • Nitric Oxide Synthase Type III
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Response Elements
  • Signal Transduction / genetics
  • Uterus / metabolism*
  • Uterus / pathology

Substances

  • Antineoplastic Agents
  • Estrogen Receptor alpha
  • Estrogens
  • Receptors, Estrogen
  • estrogen receptor alpha, human
  • Estradiol
  • Luciferases
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III