Distinct function of androgen receptor coactivator ARA70α and ARA70β in mammary gland development, and in breast cancer.
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.
Wu
Xinyu
X
Department of Pathology, New York University School of Medicine, 423 E. 23rd street, Room6139 N, New York, NY 10010, USA.
Chen
Fei
F
Sahin
Aysegul
A
Albarracin
Constance
C
Pei
Zhiheng
Z
Zou
Xuanyi
X
Singh
Baljit
B
Xu
Ruliang
R
Daniels
Garrett
G
Li
Yirong
Y
Wei
Jianjun
J
Blake
Marvin
M
Schneider
Robert J
RJ
Cowin
Pamela
P
Lee
Peng
P
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
C508724:NcoA4 protein, mouse; D056918:Nuclear Receptor Coactivators; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D008156:Luciferases