The androgen receptor (AR) is even more widely expressed in breast cancer (BC) than estrogen receptor alpha (ER) or progesterone receptor (PR), yet we still understand relatively little about its role or its potential as a therapeutic taget in the main subtypes of BC (ER+, Her2+ and triple negative). Thus, the long-term goal of this proposal is to determine how AR interacts with other pathways in BC subtypes, particularly in tumors that exhibit de novo or acquired resistance to current therapies. The objective is to utiliz old and new generation anti-androgens with different modes of action to elucidate the unique roles of AR and identify cooperating pathways to target in combination with AR. The central hypothesis is that AR plays subtype-specific roles and cooperates in different ways with proteins/pathways that drive these three main subtypes. Preliminary data demonstrate that AR plays crucial, subtype-specific roles in BC. The following specific aims will test the central hypothesis:
Aim 1. Elucidate the mechanism of action by which AR affects ER activity. Our working hypothesis is that nuclear AR is essential for E2/ER-driven proliferation in ER+/AR+ BC.
Aim 2. Identify mechanisms by which AR affects Her2+ BC. Liganded AR upregulates Her3 in some Her2+ BC lines; however, in many others Her3 is not affected, yet anti-androgens still inhibit proliferation. Thus, our working hypothesis is that there are novel mechanisms of action whereby AR impacts Her2+BC.
Aim 3. Determine the mechanisms by which AR supports survival and maintains a tumor initiating population to facilitate metastasis of AR+ TNBC. Determining how AR functions in BC subtypes and identification of previously unknown targetable pathways with which AR interacts, will lead to novel therapeutic strategies. Our studies challenge the dogma that AR and androgens are protective in breast cancer. We propose that like ER, AR is an indicator of a more well-differentiated type of tumor; however, it can most certainly drive BC growth and progression, and therefore represents a logical therapeutic target. .
The proposed research investigating the role of the androgen receptor (AR) in breast cancer (BC) is relevant to public health because it will provide fundamental knowledge regarding nuclear hormone receptor action in BC and apply that knowledge towards improving treatment of this disease and reducing mortality. Since AR is even more widely expressed than estrogen receptors in BC, knowledge regarding AR and overlapping proteins/pathways that intersect with the AR pathway in different subtypes of BC will lead to novel therapeutic strategies. Indeed, for a subset of triple negative BC, for which there is, to date, no targeted therapy, anti-androgens may serve as a much-needed targeted approach for this aggressive BC subtype.
