Role of Androgen on Breast Cancer Development and Treatment

Role of Androgen on Breast Cancer Development and Treatment Hung-Yun Lin, Ph.D. Plasma testosterone concentrations appear to correlate with breast cancer risk among postmenopausal hormone users. High baseline levels of serum testosterone have emerged as a strong prognostic factor for contralateral breast cancer, distant metastasis and local relapse. Epidemiologic studies also suggest that elevated testosterone levels are significantly associated with breast cancer risk in pre- and postmenopausal women. The mechanisms by which androgen influences breast cancer progression remain unclear. o The testosterone metabolite, dihyrotestosterone (DHT, 10- M), induces cell proliferation in both ER-positive and -negative breast cancer cell lines. In addition, DHT inhibits p53 phosphorylation and apoptosis induced by a naturally occurring stilbene, resveratrol is shown to induce apoptosis in several cancers including breast cancer cells. We hypothesize that a) androgen is a permissive factor in the growth of breast cancer cells; b) PI-3K and ERK1/2 activation are involved in androgen-induced breast cancer proliferation; and c) androgen interferes with efficacy of chemotherapeutic agents. Specific Aims: 1. To characterize the signal transduction pathways activated by dihydrotestosterone involved in proliferation of breast cancer cells; 2. To model the mechanisms by which dihydrotestosterone affects resveratrol-induced p53-dependent apoptosis in breast cancer cells. To characterize the signal transduction pathways activated and genes induced by androgen involved in proliferation of breast cancer cells (aim 1), we will use siRNA transfection and inhibitors of PI-3K or ERK1/2 to confirm that in addition to Ras-MAPK signal transduction pathways, PI3kinas/Akt kinase pathway is shared by androgen-induced proliferation of both ER-positive/ER-negative breast cancer cells. In addition, we will model the mechanisms of androgen’s effect on resveratrol-induced p53-dependent apoptosis in breast cancer cells (aim 2). To elucidate the effect of androgen on resveratrol-induced p53-dependent apoptosis, we will measure p53 abundance by real-time PCR and Western blot analysis; p53 phosphorylation by Western blot analysis; p53-dependent transcription by ChIP, RT-PCR and cell counts. This proposal investigates the effects of androgen on breast cancer development and inhibitory effect of androgen on chemotherapeutic efficacy. Understanding the mechanisms involved in the action of androgen on breast cancer occurrence and development, in addition to effect of androgen on chemopreventive agent such as resveratrol-induced p53-dependent apoptosis, will permit development of a novel and potentially beneficial approach to the treatment of breast cancer.