title: Distinct function of androgen receptor coactivator ARA70α and ARA70β in mammary gland development, and in breast cancer.
abstract: Steroid receptor coactivators are important in regulating the function of the receptors in endocrine organ development and in cancers, including breast. Androgen receptor (AR) coactivator ARA70, was first identified as a gene fused to the ret oncogene and later characterized as an AR coactivator. We previously reported that the full length ARA70α functions as a tumor suppressor gene and that ARA70β functions as an oncogene in prostate cancer. Here we show that both ARA70α and ARA70β function as AR and estrogen receptor (ER) coactivators in breast cancer cells. However, ARA70α and ARA70β serve different functions in mammary gland development and breast cancer tumorigenesis. We observed hypoplastic development of mammary glands in MMTV driven ARA70α transgenic mice and overgrowth of mammary glands in ARA70β transgenic mice at virgin and pregnant stages. We determined that ARA70α inhibited cell proliferation, and that ARA70β promotes proliferation in MCF7 breast cancer cells. These effects were observed in hormone-free media, or in media with androgen or estrogen, though to varying degrees. Additionally, we observed that ARA70β strongly enhanced the invasive ability of MCF7 breast cancer cells in in vitro Matrigel assays. Significantly, decreased ARA70α expression is associated with increased tendency of breast cancer metastasis. In summary, ARA70α and ARA70β have distinct effects in mammary gland development and in the progression of breast cancer.
authors.affiliation: Department of Pathology, New York University School of Medicine, 423 E. 23rd street, Room6139 N, New York, NY 10010, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wu
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Aysegul
authors.initials: A
authors.lastname: Sahin
authors.forename: Constance
authors.initials: C
authors.lastname: Albarracin
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Pei
authors.forename: Xuanyi
authors.initials: X
authors.lastname: Zou
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Ruliang
authors.initials: R
authors.lastname: Xu
authors.forename: Garrett
authors.initials: G
authors.lastname: Daniels
authors.forename: Yirong
authors.initials: Y
authors.lastname: Li
authors.forename: Jianjun
authors.initials: J
authors.lastname: Wei
authors.forename: Marvin
authors.initials: M
authors.lastname: Blake
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
authors.forename: Pamela
authors.initials: P
authors.lastname: Cowin
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D056918:Nuclear Receptor Coactivators / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C508724:NcoA4 protein, mouse; D056918:Nuclear Receptor Coactivators; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D008156:Luciferases