Role of Androgen Receptor in Breast Cancer Progression

已知雄激素受体（AR）在大多数雌激素受体（ER）α阳性肿瘤中表达。 人类乳腺肿瘤通过基因表达谱分析，我们发现在临床中AR RNA升高， 对他莫昔芬抗雌激素治疗耐药的乳腺肿瘤。我们已经证明过表达 AR导致ER α阳性MCF-7乳腺癌细胞对生长抑制剂产生抗性， Tam和雌激素戒断的影响，其模拟了芳香酶抑制剂的治疗作用 [Als]）。这种内分泌抵抗可被AR拮抗剂比卡鲁胺或AR逆转。 击倒。此外，在AR过度表达的乳腺癌细胞中，Tam诱导而不是抑制了 ER α的转录活性，这也可以被比卡鲁胺逆转。 因此，我们假设AR过表达是对ER靶向药物耐药的一种新机制。 治疗我们开展了这项转化研究，以扩展这些发现，以确定AR如何导致 对Tam和Als的抗性，从而鉴定抗性的潜在预测标志物和可能的 逆转耐药性的中间靶点，并最终在初步临床试验中使用 比卡鲁胺恢复肿瘤对Tam或Al耐药的乳腺癌患者的应答 治疗我们的目标是：（1）确定AR串扰与生长因子的贡献 受体和ER α在与AR过表达相关的耐药表型中使用各种信号 转导抑制剂和细胞生物学测定。(2)为了确定AR过表达如何导致Tarn介导的 核ER转录激活，探索基因组AR作用。(3)要检查AR如何 过表达影响雌激素剥夺与铝的生存途径。（4）为了确定是否 AR拮抗剂比卡鲁胺可逆转进展中的乳腺癌患者的内分泌抵抗， 在Phasei/II期临床试验中使用Tam或Al。这些研究将采用技术来探索分子 AR在乳腺癌细胞中的作用机制，这是一个研究不足的领域。我们将确定是否 AR信号通路的特定组分可用于逆转内分泌抗性。我们 预计AR将成为内分泌抗性的一个重要的新标志物， 一种FDA批准的阻断其作用的药物（比卡鲁胺），我们可以迅速将我们的结果转化为可能的 维持乳腺癌患者内分泌治疗益处的新策略。

The androgen receptor (AR) is known to be expressed in the majority of estrogen receptor (ER) alphapositive human breast tumors. By gene expression profiling, we discovered elevated AR RNA in clinical breast tumors resistant to antiestrogen therapy with tamoxifen (Tarn). We have shown that overexpression of AR causes ER alpha-positive MCF-7 breast cancer cells to become resistant to the growth-inhibitory effects of Tam and to estrogen withdrawal, which models the therapeutic action of aromatase inhibitors [Als]). This endocrine resistance could be reversed by the AR antagonist bicalutamide, or by AR knockdown. Furthermore, in AR-overexpressing breast cancer cells, Tam induced rather than repressed ERalpha's transcriptional activity, and this could also be reversed by bicalutamide. We therefore hypothesize that AR overexpression is a novel mechanism of resistance to ER-targeted therapies. We have developed this translational study to extend these findings, to determine how AR causes resistance to Tam and Als and thus identify potential predictive markers for resistance and possible intermediate targets for reversing resistance, and finally to test this hypothesis in an initial clinical trial using bicalutamide to restore response in breast cancer patients whose tumors become resistant to Tam or Al treatment. Our proposed Aims are: (1) To determine the contribution of AR crosstalk with growth factor receptors and ER alpha in the resistant phenotype associated with AR overexpression using various signal transduction inhibitors and cell biological assays. (2) To determine how AR overexpression causes Tarnmediated nuclear ER transcriptional activation, exploring genomic AR actions. (3) To examine how AR overexpression affects survival pathways during estrogen deprivation with an Al. (4) To determine whether the AR antagonist bicalutamide can reverse endocrine resistance in breast cancer patients progressing on Tam or an Al in a Phasei/ll clinical trial. These studies will employ techniques to explore the molecular mechanisms of AR action in breast cancer cells, which is an understudied area. We will identify whether specific components of the AR signaling pathway can be exploited to reverse endocrine resistance. We anticipate that AR will become an important new marker of endocrine resistance, and with the availability of an FDA-approved agent to block its effects (bicalutamide), we can rapidly translate our results into a possible new strategy for maintaining the benefits of endocrine therapy in breast cancer patients.