High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene.
The gene encoding AIB1, an estrogen receptor coactivator, is amplified in a subset of human breast cancers. Here we show that overexpression of AIB1 in transgenic mice (AIB1-tg) leads to mammary hypertrophy, hyperplasia, abnormal postweaning involution, and the development of malignant mammary tumors. Tumors are also increased in other organs, including the pituitary and uterus. AIB1 overexpression increases mammary IGF-I mRNA and serum IGF-I protein levels. In addition, IGF-I receptor and downstream signaling molecules are activated in primary mammary epithelial cells and mammary tumor cells derived from AIB1-tg mice. Knockdown of AIB1 expression in cultured AIB1-tg mammary tumor cells leads to reduced IGF-I mRNA levels and increased apoptosis, suggesting that an autocrine IGF-I loop underlies the mechanism of AIB1-induced oncogenesis.
Torres-Arzayus
Maria I
MI
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Font de Mora
Jaime
J
Yuan
Jing
J
Vazquez
Francisca
F
Bronson
Roderick
R
Rue
Montserrat
M
Sellers
William R
WR
Brown
Myles
M
D000123:Acetyltransferases; D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation; D005260:Female; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D051548:Histone Acetyltransferases; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D009857:Oncogenes; D011247:Pregnancy; D015534:Trans-Activators / Q000235:genetics*; D014407:Tumor Cells, Cultured
D015513:Oncogene Proteins; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D038362:Glycogen Synthase Kinase 3