title: The effect of estradiol on in vivo tumorigenesis is modulated by the human epidermal growth factor receptor 2/phosphatidylinositol 3-kinase/Akt1 pathway.
abstract: To determine whether the epidermal growth factor receptor 2 (ErbB2) and Akt1 can alter the in vivo growth of MCF-7 cells, parental cells or cells stably transfected with constitutively active Akt1 (myr-Akt1) or dominant-negative Akt1 mutants (K179M-Akt1 and R25C-Akt1) were implanted into athymic nude mice. Tumor growth was monitored in the presence or absence of the antiestrogen tamoxifen and the selective ErbB2 inhibitor, AG825. MCF-7 [parental or empty vector transfected, cytomegalovirus (CMV)] and myr-Akt1 cells formed tumors upon estradiol supplementation after 20-30 d (59-, 29-, and 17-fold increase in tumor volume, respectively). Tamoxifen and AG825 blocked the estradiol effect by 93 and 96% in MCF-7 xenografts, 88 and 81% in CMV xenografts, and 91% in myr-Akt1 xenografts. Furthermore, AG825 suppressed the growth of established tumors in CMV and myr-Akt1 inoculated animals by 68 and 75%, respectively, as compared with continued estrogen supplementation, suggesting a role for ErbB2. When K179M-Akt1 or R25C-Akt1 cells were injected into ovariectomized animals, tumor growth was reduced upon estradiol treatment by 95% and 98%, respectively, supporting a role for Akt1. In contrast to ovariectomized animals, in intact animals, myr-Akt1 cells could establish tumors without estradiol priming after 40-50 d (20-fold increase in tumor volume). Loss of Akt1 phosphorylation was associated with tumor growth inhibition. Immunohistochemical assays showed that in tumors from parental and CMV xenografts, estradiol decreased estrogen receptor-alpha expression and induced progesterone receptor expression and Akt phosphorylation, effects that were inhibited by tamoxifen, AG825, and R25C-Akt1 by 89, 82, and 77% for progesterone receptor expression and 48, 66, and 73% for pAkt expression, respectively. Cumulatively, our results suggest that Akt1 and ErbB2 are involved in in vivo tumorigenesis and modulation of estrogen receptor-alpha expression and activity.
authors.affiliation: Department of Human Science, School of Nursing and Health Studies, Department of Oncology, Georgetown University, 3700 Reservoir Road NW, Washington, D.C. 20057-1107, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lehnes
authors.forename: Abigail D
authors.initials: AD
authors.lastname: Winder
authors.forename: Camille
authors.initials: C
authors.lastname: Alfonso
authors.forename: Natasha
authors.initials: N
authors.lastname: Kasid
authors.forename: Michael
authors.initials: M
authors.lastname: Simoneaux
authors.forename: Heather
authors.initials: H
authors.lastname: Summe
authors.forename: Elisha
authors.initials: E
authors.lastname: Morgan
authors.forename: Mary C
authors.initials: MC
authors.lastname: Iann
authors.forename: Jessica
authors.initials: J
authors.lastname: Duncan
authors.forename: Matthew
authors.initials: M
authors.lastname: Eagan
authors.forename: Raluca
authors.initials: R
authors.lastname: Tavaluc
authors.forename: Charles H
authors.initials: CH
authors.lastname: Evans
authors.forename: Robert
authors.initials: R
authors.lastname: Russell
authors.forename: Antai
authors.initials: A
authors.lastname: Wang
authors.forename: Fengming
authors.initials: F
authors.lastname: Hu
authors.forename: Adriana
authors.initials: A
authors.lastname: Stoica
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010052:Ovariectomy; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D052160:Benzothiazoles; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C098214:tyrphostin AG825; C494918:AKT1 protein, human