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

http://www.ncbi.nlm.nih.gov/pubmed/20577047

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.

Pubmed ID: 20577047 RIS Download

Mesh terms: Animals | Antineoplastic Agents | Breast Neoplasms | Cell Line, Tumor | Cell Nucleus | Cell Proliferation | Endometrial Neoplasms | Enzyme Activation | Estradiol | Estrogen Receptor alpha | Estrogens | Female | Humans | Luciferases | Mice | Mice, Nude | Nitric Oxide Synthase Type III | Receptors, Estrogen | Response Elements | Signal Transduction | Uterus

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Associated grants

  • Agency: NCI NIH HHS, Id: CA18119
  • Agency: NIDDK NIH HHS, Id: DK15556
  • Agency: NIDDK NIH HHS, Id: DK56930
  • Agency: NICHD NIH HHS, Id: HD30276
  • Agency: Intramural NIH HHS, Id:

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