title: Estrogen-dependent and estrogen-independent mechanisms contribute to AIB1-mediated tumor formation.
abstract: We have previously reported the oncogenic properties of the gene amplified in breast cancer 1 (AIB1), a member of the p160 family of hormone receptor coactivators. In a transgenic mouse model, AIB1 overexpression resulted in a high incidence of tumors in various tissues, including mammary gland, uterus, lung, and pituitary. To determine whether the AIB1 oncogenicity in this model depended on its function as an estrogen receptor (ER) coactivator, we abolished ER signaling through two independent approaches, by performing ovariectomy on AIB1 transgenic (AIB1-tg) mice to prevent gonadal estrogen production and by crossing AIB1-tg mice with ERalpha-null mutant mice. Ovariectomized (ovx) mice, but not AIB1 x ERalpha-/- mice, still developed mammary gland hyperplasia and ductal carcinoma in situ. Both approaches, however, completely prevented the development of invasive mammary tumors, indicating that invasive mammary tumor formation is strictly estrogen dependent. Once developed, AIB1-induced mammary tumors can subsequently lose their dependence on estrogen: Injection of ERalpha(+) tumor cell lines derived from such tumors into ovx or untreated wild-type mice resulted in a similar rate of tumor growth in both groups. Surprisingly, however, ovx mice had an approximately 4-fold higher rate of metastasis formation, suggesting that estrogen provided some protection from metastasis formation. Lastly, our experiments identified oncogenic functions of AIB1 that are independent of its ER coactivation, as both approaches, ovariectomy and ER-/- crosses, still resulted in a high incidence of tumors in the lung and pituitary. We therefore conclude that AIB1 can exert its oncogenicity through tissue-specific estrogen-dependent and estrogen-independent functions.
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Torres-Arzayus
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015994:Incidence; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D056921:Nuclear Receptor Coactivator 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3