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The Role of Androgen Receptor Signaling in the Breast: Potential Disruption by Synthetic Progestins Used in Hormone Replacement Therapy
Background. Signaling through the androgen receptor (AR) is required for normal development of the breast, and suppresses growth of breast cancer cells, at least in part by inhibiting estrogen receptor-alpha (ER) activity. We propose that there is a critical balance between AR and ER action in the normal breast, and that perturbation of this balance promotes uncontrolled cell growth. Our research suggests that the protective effects of AR signaling in the breast may be disrupted by synthetic progestins used in hormone replacement therapy (HRT), such as medroxyprogesterone acetate (MPA). MPA binds with high affinity to AR and inhibits its function, which could contribute to the increased breast cancer risk in women on HRT. Hypothesis. We propose that AR signaling in normal human breast cells inhibits proliferation and ER signaling; and can be disrupted by synthetic progestins. Specific Aims. 1. To assess levels and activity of AR in cultured normal human breast, and relate AR function to proliferation and estrogen signaling. 2. To determine the effects of synthetic progestins on AR function in the breast. Study Design. We will use a novel method of culturing normal human breast tissue, obtained from reduction mammoplasties or mastectomies, which retains the tissue structure and steroid responsiveness. In Aim 1, tissues will be cultured for varying periods in the absence or presence of estradiol, the native androgen dihydrotestosterone (DHT), or both. Tissues will be analysed for proliferation, apoptosis and AR/ER expression. Receptor antagonists will be used to assess the role of AR and ER in responses observed. Interaction between AR and ER will be analyzed by coimmunoprecipitation and confocal microscopy, and microarray analysis will be performed on cDNA from microdissected cells to detect expression of AR or ER-regulated genes. In Aim 2 we will characterize the effect of MPA and other synthetic progestins on AR function, using mammalian two-hybrid analysis, radioligand binding and reporter gene assays. We will also determine whether progestins can disrupt AR signaling, and abolish the protective effect of AR on ER signaling, in the normal breast model. Potential Outcomes and Benefits. Our studies will address for the first time whether AR signaling plays a protective role in regulation of proliferation and ER signaling in the normal human breast. A better understanding of the effects of synthetic progestins on AR signaling may provide a mechanistic basis for the increased breast cancer risk associated with their use in HRT, and lead to new prevention strategies.
The female sex hormones, or estrogens, control growth and development of the normal breast. Various treatments have been developed which aim to block the stimulatory effects of estrogens in breast cancer cells, and the last 10 years have produced tremendous breakthroughs with the development of new hormonal agents for both the treatment and prevention of cancer. On the other hand, hormone replacement therapy (HRT), in which a combination of estrogens and drugs called synthetic progestins are administered to millions of women worldwide to relieve menopausal symptoms, has recently been associated with an increased risk of developing breast cancer. In addition to estrogens, other hormones also contribute to normal breast development and appear to influence the formation of breast cancer. One such group of hormones is the androgens. All women have significant levels of androgens in their body and it appears that they act in concert with estrogens and progestins to regulate breast cancer growth. Evidence for the importance of these hormones is the frequent presence of androgen receptors (ARs), which mediate the effect of androgens, in breast cancers. Our research has shown that the AR is an important regulator of hormone action in breast cancer, and that androgens oppose the effects of estrogens in breast cancer cells to inhibit their growth. A disturbance in this important balance between androgens and estrogens could lead to uncontrolled estrogen action in the breast, thereby promoting the growth of breast cancer. However, we still do not understand the role of androgens in the development of the normal breast, and whether perturbations in this hormone signaling pathway might affect a woman’s risk of developing breast cancer. The major objective of our study is to investigate the role of androgen signaling in normal human breast, and its balance with estrogen signaling, using a unique model of cultured normal breast tissue that allows the tissue to keep its natural structure and maintain hormone responsiveness. We will also investigate whether synthetic progestins (such as those used in HRT), which we have shown can bind to the AR and inhibit its activity, affect this estrogen/androgen balance by disrupting androgen signaling in the breast. We believe that a better understanding of androgen signaling in the breast will give us an insight into the mechanisms underlying the increased risk of breast cancer in women taking HRT, and ultimately lead to better preventative strategies.