title: 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.affiliation: Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063, USA.
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.forename: Sarah
authors.initials: S
authors.lastname: Oltmann
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Konaniah
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.forename: Gail D
authors.initials: GD
authors.lastname: Thomas
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Madak-Erdogan
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
authors.forename: Sean P
authors.initials: SP
authors.lastname: Dineen
authors.forename: Christina L
authors.initials: CL
authors.lastname: Roland
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: Benita S
authors.initials: BS
authors.lastname: Katzenellenbogen
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D004958:Estradiol / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D052250:Nitric Oxide Synthase Type III; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics; D014599:Uterus / Q000378:metabolism* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011960:Receptors, Estrogen; D004958:Estradiol; D008156:Luciferases; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III