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

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.

• Authors: Ken L Chambliss, Qian Wu, Sarah Oltmann, Eddy S Konaniah, Michihisa Umetani, Kenneth S Korach, Gail D Thomas, Chieko Mineo, Ivan S Yuhanna, Sung Hoon Kim, Zeynep Madak-Erdogan, Adriana Maggi, Sean P Dineen, Christina L Roland, David Y Hui, Rolf A Brekken, John A Katzenellenbogen, Benita S Katzenellenbogen, Philip W Shaul
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 7 Pg. 2319-30 (Jul 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20577047 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• ESR1 protein, human
• Estrogen Receptor alpha
• Estrogens
• Receptors, Estrogen
• Estradiol
• Luciferases
• NOS3 protein, human
• Nitric Oxide Synthase Type III

Topics

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