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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

基本信息

批准号：
9104116
负责人：
Jennifer Richer-Mouchantat
金额：
$ 35.57万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/9104116
关键词：
AREG gene Affect Androgen Antagonists Androgen Receptor Androgens Aromatase Inhibitors Bicalutamide Biology Cell Nucleus Cells Clinical Data Clinical Trials Critical Pathways DNA Binding Data Disease ERBB2 gene Endocrine Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits Fulvestrant Gene Proteins Generations Goals Growth Health Hormone Receptor Knowledge Lead Ligands Link Modeling Neoplasm Metastasis Nuclear Nuclear Hormone Receptors Nurses&apos Health Study Outcome Pathway interactions Play Population Progesterone Receptors Proteins Public Health Receptor Signaling Research Resistance Role Signal Pathway Suspension substance Suspensions Tamoxifen Testing Therapeutic Work base cancer subtypes improved in vitro testing in vivo knock-down malignant breast neoplasm mortality novel novel therapeutics receptor expression receptor function targeted treatment therapeutic target tool traditional therapy triple-negative invasive breast carcinoma tumor

项目摘要

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. .