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Androgen receptor status as a determinant of breast cancer risk and disease progression.
Tumor Cell Biology II
Background: Despite the impact of breast cancer on quality of life and life expectancy of women, the critical determinants of breast cancer remain enigmatic. There have been significant advances in the management of breast cancer, with tamoxifen and more recently the use of aromatase inhibitors, in the adjuvant setting, impacting on current breast cancer management practices. However, there is still a subset of patients that do not respond, or initially respond but later relapse with current estrogen therapies. The importance of the estrogen receptor (ER) signaling pathway in breast cancer has been well characterized and utilized as a therapeutic target. Testosterone is an essential prohormone for both estradiol and 5a-dihydrotestosterone (DHT), and the intracellular mediator of DHT, the androgen receptor (AR), is expressed more frequently than ER in breast cancer and is the sole steroid receptor expressed in 25% of metastatic breast tumors. DHT can inhibit the growth of breast cancer cells and this inhibition occurs via the AR. Objective/Hypothesis: Alterations in AR signaling increases the risk of developing breast cancer and subsequent progression of the disease. Specific Aims : 1. To determine whether a reduction in AR signaling is associated with breast cancer aggressiveness at diagnosis. 2. To determine whether alterations in AR signaling in non malignant breast tissue is associated with breast cancer development. Study Design: Levels of AR (by immunohistochemisty (IHC)) and AR function (IHC of AR regulated proteins), will be quantitated using immuno-stained breast cancer sections from a cohort of 194 unselected invasive breast cancers with known outcome. The relationship between AR status and disease progression and aggressiveness and other established clinical parameters of outcome (eg nodal status, ER, PR) will be evaluated. AR status will also be assessed in a novel cohort obtained from women identified through a national mammogram screening program. Alterations in AR signaling will be assessed in nonmalignant tissue and related to breast density, a surrogate marker for breast cancer risk. Potential Outcomes and Benefits: The proposed study will determine whether there is a relationship between AR and breast cancer development and progression. Demonstration of a relationship between AR status and breast density would have implications for development of chemopreventive studies for women with increased risk of developing breast cancer.
Current hormonal therapies for the treatment of breast cancer target the cellular mediator of the female sex hormone estrogen, the estrogen receptor (ER), since breast cells rely on estrogen for growth and survival. Unfortunately, not all women respond to antiestrogen treatments, and many that initially respond will relapse with advanced disease that is no longer responsive to hormonal therapies. More recently, the potentially important role of other sex hormones in breast development, such as the commonly perceived male sex hormone androgen (ie testosterone, which is the critical precursor for estrogen in women), and its mediator the androgen receptor (AR) has been recognized. The AR is expressed more frequently in breast cancers than ER, and is expressed in 25% of metastatic lesions which are negative for ER. There is emerging evidence that the AR has an important role in normal breast development, breast cancer progression and aggressiveness, and that AR signaling can be disrupted by synthetic progestins, such as those used in hormone replacement therapy or oral contraceptives. Our objective is to determine whether alterations in AR levels or function increases the risk of developing breast cancer and subsequent progression of the disease. Specifically, we aim to assess whether levels of AR in breast tumors are associated with the aggressiveness of the disease at diagnosis. We also aim to determine whether alterations in AR (and/or ER) levels or function in non malignant breast tissue is associated with the development of breast cancer. Potential outcomes of the study are that AR measures could be developed as an indicator of risk of developing breast cancer, and of the hormone responsiveness of established breast tumors. Ultimately, the AR signaling pathway could be used as a therapeutic target, especially in metastatic breast cancers that are ER negative but AR positive, and/or as a chemopreventive target.