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- Title
Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice.
- Authors
Chambliss, Ken L.; Qian Wu; Oltmann, Sarah; Konaniah, Eddy S.; Umetani, Michihisa; Korach, Kenneth S.; Thomas, Gail D.; Mineo, Chieko; Yuhanna, Ivan S.; Sung Hoon Kim; Madak-Erdogan, Zeynep; Maggi, Adriana; Dineen, Sean P.; Roland, Christina L.; Hui, David Y.; Brekken, Rolf A.; Katzenellenbogen, John A.; Katzenellenbogen, Benita S.; Shaul, Philip W.; Wu, Qian
- 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.
- Subjects
NUCLEAR receptors (Biochemistry); STEROID hormones; TRANSCRIPTION factors; CELL proliferation; CELL migration; LABORATORY mice; PROTEIN metabolism; ANIMAL experimentation; ANTINEOPLASTIC agents; BIOCHEMISTRY; BREAST tumors; CELL lines; CELL nuclei; CELL physiology; CELLULAR signal transduction; COMPARATIVE studies; DNA; ESTRADIOL; ESTROGEN; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MICE; OXIDOREDUCTASES; PROTEINS; RESEARCH; UTERUS; ENDOMETRIAL tumors; EVALUATION research
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 7, p2319
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI38291