Androgen Receptor and Intersecting Pathways Critical to Breast Cancer Subtypes

 描述(申请人提供)：雄激素受体(AR)在乳腺癌(BC)中的表达甚至比雌激素受体(ER)或孕激素受体(PR)更广泛，但我们对其在BC的主要亚型(ER+、Her2+和三阴性)中的作用或作为治疗标记物的潜力了解相对较少。因此，这项建议的长期目标是确定AR如何与BC亚型中的其他途径相互作用，特别是在对当前治疗表现出从头或获得性耐药的肿瘤中。目的是利用具有不同作用模式的新一代抗雄激素来阐明AR的独特作用，并找出与AR联合靶向的协同途径。中心假说是，AR扮演着亚型特有的角色，并以不同的方式与驱动这三个主要亚型的蛋白质/途径合作。初步数据表明，AR在BC中发挥着关键的、亚型特有的作用。目的1.阐明AR影响ER活性的作用机制。我们的工作假设是，在ER+/AR+BC中，核AR对于E2/ER驱动的增殖是必不可少的。目的2.明确AR影响Her2+BC的机制。在一些Her2+BC细胞系中，配基AR上调HER3；然而，在许多其他细胞系中，HER3不受影响，但抗雄激素仍然抑制其增殖。因此，我们的工作假设是存在AR影响Her2+BC的新的作用机制。目的3.确定AR支持生存和维持肿瘤起始群体以促进AR+TNBC转移的机制。确定AR如何在BC亚型中发挥作用，并确定以前未知的与AR相互作用的靶向通路，将导致新的治疗策略。我们的研究挑战了AR和雄激素在乳腺癌中具有保护作用的教条。我们认为，与ER一样，AR是分化更好的肿瘤类型的指标；然而，它几乎肯定可以推动BC的生长和进展，因此代表了一个合理的治疗靶点。。

 DESCRIPTION (provided by applicant): 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. .