Role of Androgen Receptor in Breast Cancer Progression

雄激素受体在乳腺癌进展中的作用

• 批准号: 7385531
• 负责人: Suzanne AW Fuqua
• 金额: $ 15.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385531
• 关键词: Affect; Agar; Androgen Receptor; Androgens; Antiestrogen Therapy; Apoptosis; Area; Aromatase; Aromatase Inhibitors; Bicalutamide; Binding; Biological Assay; Biological Markers; Biopsy; Breast Cancer Cell; Cancer Patient; Cathepsins; Cell Cycle; Cell Line; Cells; Clinical; Clinical Research; Clinical Trials; Condition; Confocal Microscopy; Cultured Cells; Cyclin D1; Endocrine; Engineering; Epidermal Growth Factor Receptor; Estrogen Nuclear Receptor; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Gene Expression Profiling; Genes; Genomics; Goals; Growth; Growth Factor; Growth Factor Receptors; Hormonal; Human; Immunoblotting; Immunoprecipitation; MAP2K1 gene; MCF7 cell; Mammary Neoplasms; Mediating; Modeling; Modification; Molecular; Mutate; Nuclear; Nude Mice; Pathway interactions; Phase; Phenotype; Progressive Disease; Protein Overexpression; RNA; Receptor Signaling; Recruitment Activity; Reporting; Resistance; Role; SRC gene; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Signaling Molecule; Soft Agar Assay; T47D; TFF1 gene; Tamoxifen; Techniques; Testing; Therapeutic; Transcriptional Activation; Transfection; Translating; Two-Hybrid System Techniques; Withdrawal; Woman; Xenograft procedure; anastrozole; c-myc Genes; chromatin immunoprecipitation; deprivation; hormone therapy; inhibitor/antagonist; malignant breast neoplasm; novel; promoter; receptor; resistance mechanism; response; translational study; tumor; tumor progression

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.

已知雄激素受体（AR）在大多数雌激素受体（ER）字母阳性中表达 人乳腺肿瘤。通过基因表达分析，我们发现临床中的AR RNA升高 对他莫昔芬（TARN）抗抗雌激素治疗的乳腺肿瘤。我们已经表明过表达 AR的导致ERα阳性MCF-7乳腺癌细胞具有抗性抑制性 TAM和提取雌激素的影响，该作用模拟了芳香酶抑制剂的治疗作用 [ALS]）。这种内分泌抗性可以通过AR拮抗剂Bicalutamide或AR逆转 击倒。此外，在过表达AR的乳腺癌细胞中，TAM诱导而不是抑制 Eralpha的转录活性，这也可以被Bicalutamide逆转。 因此，我们假设AR过表达是一种对ER靶向的抗性的新机制 疗法。我们已经开发了这项翻译研究来扩展这些发现，以确定AR的原因 对TAM和ALS的耐药性，从而确定了抗性的潜在预测标记和可能的预测标记 逆转电阻的中间目标，最后在初始临床试验中检验该假设 dicalutamide可以恢复乳腺癌患者的反应，其肿瘤对TAM或AL具有抗 治疗。我们提出的目标是：（1）确定AR串扰与生长因子的贡献 使用各种信号与AR过表达相关的抗性表型中的受体和ERα 转导抑制剂和细胞生物学测定。 （2）确定AR过表达如何导致损坏的 核ER转录激活，探索基因组AR作用。 （3）检查AR如何 过表达会影响雌激素剥夺期间的生存途径。 （4）确定是否 AR拮抗剂Bicalutamide可以在乳腺癌患者中逆转内分泌耐药性 TAM或AL临床试验中的AL。这些研究将采用技术来探索分子 乳腺癌细胞中AR作用的机制，这是一个研究的区域。我们将确定是否 AR信号通路的特定组件可以被利用为反向内分泌抗性。我们 预计AR将成为内分泌抗性的重要新标记，并随着 FDA批准的代理以阻止其效果（Bicalutamide），我们可以将结果迅速转化为可能 维持内分泌疗法对乳腺癌患者的好处的新策略。