title: Developmental stage determines estrogen receptor alpha expression and non-genomic mechanisms that control IGF-1 signaling and mammary proliferation in mice.
abstract: Insulin like growth factor-1 (IGF-1) stimulates increased proliferation and survival of mammary epithelial cells and also promotes mammary tumorigenesis. To study the effects of IGF-1 on the mammary gland in vivo, we used BK5.IGF-1 transgenic (Tg) mice. In these mice, IGF-1 overexpression is controlled by the bovine keratin 5 promoter and recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 that is seen in women. Studies have shown that BK5.IGF-1 Tg mice are more susceptible to mammary tumorigenesis than wild-type littermates. Investigation of the mechanisms underlying increased mammary cancer risk, reported here, revealed that IGF-1 preferentially activated the PI3K/Akt pathway in glands from prepubertal Tg mice, resulting in increased cyclin D1 expression and hyperplasia. However, in glands from postpubertal Tg mice, a pathway switch occurred and activation of the Ras/Raf/MAPK pathway predominated, without increased cyclin D1 expression or proliferation. We further showed that in prepubertal Tg glands, signaling was mediated by formation of an ERα/IRS-1 complex, which activated IRS-1 and directed signaling via the PI3K/Akt pathway. Conversely, in postpubertal Tg glands, reduced ERα expression failed to stimulate formation of the ERα/IRS-1 complex, allowing signaling to proceed via the alternate Ras/Raf/MAPK pathway. These in vivo data demonstrate that changes in ERα expression at different stages of development direct IGF-1 signaling and the resulting tissue responses. As ERα levels are elevated during the prepubertal and postmenopausal stages, these may represent windows of susceptibility during which increased IGF-1 exposure maximally enhances breast cancer risk.
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Tian
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Berton
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Shirley
authors.forename: Isabel
authors.initials: I
authors.lastname: Lambertz
authors.forename: Irma B
authors.initials: IB
authors.lastname: Gimenez-Conti
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Conti
authors.forename: Robin
authors.initials: R
authors.lastname: Fuchs-Young
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D019899:Paracrine Communication; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012741:Sexual Maturation; D015398:Signal Transduction
chemical_list: C530105:Ccnd1 protein, mouse; D047628:Estrogen Receptor alpha; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D019938:Cyclin D1; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D019908:Proto-Oncogene Proteins c-raf