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

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

Research output: Contribution to journalArticle

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-Gaαi 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.

Original languageEnglish (US)
Pages (from-to)2319-2330
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
StatePublished - Jul 1 2010

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Uterine Neoplasms
Dendrimers
Estrogen Receptors
Estrogens
Breast Neoplasms
Growth
Steroid Receptors
Estradiol
Hormones
Selective Estrogen Receptor Modulators
Enzyme Activation
MCF-7 Cells
Response Elements
Endometrial Neoplasms
Luciferases
Carotid Arteries
GTP-Binding Proteins
Heterografts
Uterus
Cell Movement

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chambliss, K. L., Wu, Q., Oltmann, S., Konaniah, E. S., Umetani, M., Korach, K. S., ... Shaul, P. W. (2010). Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. Journal of Clinical Investigation, 120(7), 2319-2330. https://doi.org/10.1172/JCI38291

Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. / 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.; Shaul, Philip W.

In: Journal of Clinical Investigation, Vol. 120, No. 7, 01.07.2010, p. 2319-2330.

Research output: Contribution to journalArticle

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 2010, 'Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice', Journal of Clinical Investigation, vol. 120, no. 7, pp. 2319-2330. https://doi.org/10.1172/JCI38291
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. ; Shaul, Philip W. / Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 7. pp. 2319-2330.
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