1. Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
- Author
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Chambliss, Ken L., Wu, Qian, Oltmann, Sarah, Konaniah, Eddy S., Umetani, Michihisa, Korach, Kenneth S., Thomas, Gail D., Mineo, Chieko, Yuhanna, Ivan S., Kim, Sung Hoon, Madak-Erdogan, Zeynep, Maggi, Adriana, Dineen, Sean P., Roland, Christina L., Hui, David Y., Brekken, Rolf A., Katzenellenbogen, John A., Katzenellenbogen, Benita S., and Shaul, Philip W.
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Estradiol -- Usage -- Health aspects -- Research ,Breast cancer -- Risk factors -- Genetic aspects -- Care and treatment -- Research ,Mice -- Usage -- Models -- Physiological aspects -- Research -- Genetic aspects -- Health aspects ,DNA binding proteins -- Genetic aspects -- Research -- Physiological aspects -- Models -- Health aspects -- Usage ,Health care industry - 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 ERα, direct ERα-Gαi 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 ERα- 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., Introduction Steroid hormone receptors (SHRs) function classically as transcription factors. More recently, it has become apparent that steroid hormones also initiate nongenomic responses via activation of a subpopulation of these [...]
- Published
- 2010
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