Androgen Receptor and Intersecting Pathways Critical to Breast Cancer Subtypes

雄激素受体和交叉途径对乳腺癌亚型至关重要

• 批准号: 9480928
• 负责人: Jennifer Richer-Mouchantat
• 金额: $ 6.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-02 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9480928
• 关键词: Affect; Androgen Antagonists; Androgen Receptor; Androgens; Critical Pathways; Data; Disease; Estrogen Receptor alpha; Estrogen Receptors; Exhibits; Generations; Goals; Growth; Knowledge; Ligands; Neoplasm Metastasis; Nuclear; Nuclear Hormone Receptors; Pathway interactions; Play; Population; Progesterone Receptors; Proteins; Public Health; Research; Resistance; Role; Testing; Therapeutic; Tumor Initiators; cancer subtypes; improved; malignant breast neoplasm; mortality; novel; novel therapeutics; public health relevance; receptor function; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor

 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. .

 描述（由申请人提供）：雄激素受体（AR）在乳腺癌（BC）中的表达甚至比雌激素受体α（ER）或孕激素受体（PR）更广泛，但我们对它在BC的主要亚型（ER+、Her 2+和三阴性）中作为治疗靶点的作用或潜力了解相对较少。因此，该提案的长期目标是确定AR如何与BC亚型中的其他途径相互作用，特别是在对当前疗法表现出新发或获得性耐药的肿瘤中。目的是利用具有不同作用模式的老一代和新一代抗雄激素来阐明AR的独特作用，并确定与AR联合靶向的合作途径。核心假设是AR发挥亚型特异性作用，并以不同方式与驱动这三种主要亚型的蛋白质/途径合作。初步数据表明，AR在BC中起着至关重要的亚型特异性作用。以下具体目标将检验中心假设：目标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。目标二。确定AR影响Her 2 + BC的机制。配体AR在一些Her 2 + BC系中上调Her 3;然而，在许多其他系中，Her 3不受影响，但抗雄激素仍抑制增殖。因此，我们的工作假设是存在AR影响Her 2 +BC的新作用机制。目标3。确定AR支持生存并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，并鉴定与AR相互作用的先前未知的靶向途径，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，像ER一样，AR是一种分化更好的肿瘤类型的指标;然而，它可以肯定地驱动BC的生长和进展，因此代表了一个合理的治疗靶点。.