Elucidating the Role of the Androgen Receptor in Breast Cancer

Abstract

Sex steroid hormones and hormone receptor signaling play a critical role in the development and progression of breast cancers. While the effects of estrogens and estrogen receptor (ER) signaling pathways in the breast are well characterized, comparatively little is known about the effects of androgens and the androgen receptor (AR). The effects of AR signaling in the breast are hypothesized to differ in estrogen-rich and estrogen-replete environments. Elucidating these effects may lead to novel opportunities for the targeted prevention or treatment of breast cancers. In this dissertation, I evaluate AR as a potential marker of breast cancer risk and prognosis, and circulating hormones as prognostic markers using the resources of the Nurses’ Health Studies. In Chapter 1, I assessed the association between AR protein expression in normal breast tissue and subsequent breast cancer risk using a nested case-control study of women with benign breast disease (78 cases, 276 controls). AR expression was not associated with breast cancer risk, nor was there heterogeneity by ER or Ki67 expression level in the normal tissue. In Chapter 2, I evaluated the association between tumor AR protein expression and survival among 4,147 women with invasive breast cancer. In the first 7 years of follow-up, AR expression was associated with improved breast cancer survival for ER+ breast cancers, and worse survival for ER- breast cancers. Moreover, a linear dose-response relationship was observed between AR expression and the breast cancer mortality rate among ER- cancers. Finally, in Chapter 3, I examined the relationship between pre-diagnostic circulating sex hormone levels and survival among 2,048 breast cancer patients. Higher estradiol levels were associated with a modest increase in the all-cause mortality rate, though testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels were not consistently associated with survival outcomes. These associations did not differ by tumor ER expression. These findings do not support a strong role of AR signaling in the development of breast cancers, but suggest that AR signaling may influence tumor progression. AR expression may have utility in the clinical management of breast cancer, if clinical trials demonstrate the efficacy and tolerability of AR-targeted therapies.