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 ARA70alpha functions as a tumor suppressor gene and that ARA70beta functions as an oncogene in prostate cancer. Here we show that both ARA70alpha and ARA70beta function as AR and estrogen receptor (ER) coactivators in breast cancer cells. However, ARA70alpha and ARA70beta serve different functions in mammary gland development and breast cancer tumorigenesis. We observed hypoplastic development of mammary glands in MMTV driven ARA70alpha transgenic mice and overgrowth of mammary glands in ARA70beta transgenic mice at virgin and pregnant stages. We determined that ARA70alpha inhibited cell proliferation, and that ARA70beta 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 ARA70beta strongly enhanced the invasive ability of MCF7 breast cancer cells in in vitro Matrigel assays. Significantly, decreased ARA70alpha expression is associated with increased tendency of breast cancer metastasis. In summary, ARA70alpha and ARA70beta have distinct effects in mammary gland development and in the progression of breast cancer.

PMID: 20814820 [PubMed - as supplied by publisher] Source: National Library of Medicine.