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

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


  • Chambliss KL
  • Wu Q
  • Oltmann S
  • Konaniah ES
  • Umetani M
  • Korach KS
  • Thomas GD
  • Mineo C
  • Yuhanna IS
  • Kim SH
  • Madak-Erdogan Z
  • Maggi A
  • Dineen SP
  • Roland CL
  • Hui DY
  • Brekken RA
  • Katzenellenbogen JA
  • Katzenellenbogen BS
  • Shaul PW


The Journal of clinical investigation

Publication Data

July 1, 2010

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:

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