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阳性中表达 人类乳房肿瘤。通过基因表达谱分析，我们发现临床上AR RNA升高 对他莫昔芬(TARN)抗雌激素治疗耐药的乳腺肿瘤。我们已经证明了过度表达 AR使ERα阳性的MCF-7乳腺癌细胞对生长抑制产生抗药性 和雌激素戒断对芳香酶抑制剂治疗作用的影响 [ALS]))。这种内分泌抵抗可被AR拮抗剂比卡鲁胺或AR逆转 击倒对手。此外，在AR过表达的乳腺癌细胞中，对其进行了诱导而不是抑制 ERpha的转录活性，这也可以被比卡鲁胺逆转。 因此，我们假设AR的过度表达是抵抗ER靶向的一种新机制 治疗。我们开发了这项翻译研究来扩展这些发现，以确定AR是如何引起的 对和ALS的抗性，从而确定潜在的抗性预测标记和可能的 逆转耐药性的中间目标，最后在最初的临床试验中验证这一假设 比卡鲁胺恢复对或铝耐药的乳腺癌患者的反应 治疗。我们提出的目标是：(1)确定AR串扰对增长因子的贡献 AR过表达相关耐药表型中的受体和ERα 转导抑制剂和细胞生物学检测。(2)确定AR过度表达是如何导致Tarnmediated的 核内ER转录激活，探索基因组AR的作用。(3)研究AR如何 在雌激素缺乏症患者中，过表达会影响生存通路。(4)确定是否 AR拮抗剂比卡鲁胺可逆转进展期乳腺癌患者的内分泌抵抗 或Al正在进行一项为期一周的临床试验。这些研究将使用技术来探索分子 AR在乳腺癌细胞中的作用机制是一个研究较少的领域。我们将确定是否 AR信号通路的特定成分可以被用来逆转内分泌抵抗。我们 预计AR将成为内分泌抵抗的重要新标记物，并随着 作为FDA批准的阻断其影响的药物(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.