Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
Ken L. Chambliss, … , Benita S. Katzenellenbogen, Philip W. Shaul
Ken L. Chambliss, … , Benita S. Katzenellenbogen, Philip W. Shaul
Published June 23, 2010
Citation Information: J Clin Invest. 2010;120(7):2319-2330. https://doi.org/10.1172/JCI38291.
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Research Article

Non-nuclear estrogen receptor α 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 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.

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

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Figure 7

Non-nuclear ER signaling does not induce a uterotrophic response or promote breast cancer tumor growth in vivo.

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Non-nuclear ER signaling does not induce a uterotrophic response or prom...
(A) Uteri from mice treated 24 days with vehicle, E2, dendrimer, or EDC. (B) Uterine wet weight/body weight ratio. In additional experiments, uteri were obtained from mice that were also treated with either ICI 182,780 (C) or pertussis toxin (D). In B–D, values are mean ± SEM, n = 8–9. *P < 0.05 versus vehicle; †P < 0.05 versus no ICI 182,780. (E) MCF-7 cell tumor xenografts were established with E2 treatment for 28 days in SCID mice, and treatment was then randomized to continue with E2 for 21 days or switched to vehicle, dendrimer, or EDC for 21 days. Representative tumors are shown in E. (F) Tumor weight at end of study. In F, values are mean ± SEM, n = 11–18. *P < 0.05 versus vehicle.