MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER

AR-ER 在乳腺癌激素抵抗和转移中的合作机制

基本信息

批准号：
9316124
负责人：
Suzanne AW Fuqua
金额：
$ 36.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-07 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316124
关键词：
Adjuvant Therapy Affect Androgen Receptor Androgens Aromatase Inhibitors Breast Cancer Patient Breast cancer metastasis Cancer Model Candidate Disease Gene Cells Clinical Collaborations Computer Simulation Databases Development Diagnosis Disease Disease Resistance Disseminated Malignant Neoplasm Distant ESR1 gene Enhancers Estrogen Receptors Estrogen receptor negative Estrogen receptor positive Estrogens Evolution Failure Gene Expression Gene Targeting Genes Genomics Growth Growth Factor Receptors Hormonal Hormones Human Knowledge Ligands Maintenance Malignant Neoplasms Mammary Neoplasms Mediating Membrane Metastatic breast cancer Modeling Mutate Mutation Neoplasm Metastasis Nuclear Receptors Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmacotherapy Pre-Clinical Model Receptor Cross-Talk Receptor Gene Receptor Signaling Recurrence Relapse Resistance Resistance development Resources Role Signal Transduction Site Tamoxifen Testing Therapeutic Therapeutic Intervention Up-Regulation Woman Work differential expression epithelial to mesenchymal transition experience hormone resistance hormone sensitivity hormone therapy in vivo innovation malignant breast neoplasm metastatic process migration mutant non-genomic novel novel strategies novel therapeutic intervention novel therapeutics overexpression predictive marker pressure prognostic promoter receptor resistance mechanism self-renewal success targeted treatment therapeutic evaluation therapy resistant tumor tumor growth tumor initiation

项目摘要

Estrogen receptor (ER)-positive breast tumors are treated with endocrine therapies which specifically target the ER. Patients can remain disease-free for many years; however, resistance to treatment eventually develops, and the majority of women will suffer a recurrence of metastatic cancer. We hypothesized that the key to the long-term treatment of women with ER-positive breast cancers was to focus on identifying novel mechanisms of resistance using metastatic tumors resistant to therapy where tumor evolution and clonal selection have occurred. We identified the androgen receptor (AR) as a new clinical target which was up regulated in resistant, metastatic tumors. We have learned that AR functionally collaborates with ER, and that resistance may be associated with a failure of hormone therapy to completely block both androgen and estrogen signaling. We have also discovered that AR-overexpressing cells become metastatic in vivo. Furthermore, we were the first to identify that the estrogen receptor ESR1 gene can be mutated in metastatic tumors; acquiring hormone-independent and endocrine therapy-resistant functions which we hypothesize will also be impacted by ligand-independent AR signaling. Importantly, cells with ESR1 mutations also up-regulate AR, demonstrating a unique relationship between these mutations and AR. Our Aims are: (1) To determine if receptor crosstalk (WT or mutant ER with AR) is a mechanism of resistance to hormonal agents, (2) To determine whether AR employs novel nuclear receptor interactions to drive hormone resistance, and (3) To determine AR and ESR1 mutant effects on invasion and metastasis. Key success has been made in developing resistant models with endogenous up regulation of AR coincident with acquired resistance, and we have already identified potential AR-mediated candidate resistance mechanisms. Undoubtedly hormone therapy resistance in patients is multifactorial and will require combination hormonal and targeted therapy along with knowledge of the activation status of key pathways, such as those arising from mutations in ER in metastatic tumors. Our work will impact a large number of women with ER-positive breast cancer who recur with therapy-resistant disease.

雌激素受体（ER） - 阳性乳腺肿瘤用内分泌疗法治疗，专门针对嗯。患者可以保持无病多年。但是，对治疗的抵抗最终会发展出来，大多数女性将遭受转移性癌症的复发。我们假设 ER阳性乳腺癌的长期治疗是专注于识别新机制使用转移性肿瘤抵抗肿瘤进化和克隆选择具有抗药性的耐药性发生。我们确定雄激素受体（AR）是一个新的临床靶标，在抗性，转移性肿瘤。我们了解到AR在功能上与ER合作，并且抵抗力可能与激素疗法失败完全阻断雄激素和雌激素有关信号。我们还发现，过表达AR的细胞在体内变为转移性。此外，我们是第一个确定雌激素受体ESR1基因可以在转移性肿瘤中突变的人。获取我们假设的抗激素独立和内分泌疗法的功能也将受到影响通过非配体无关的AR信号传导。重要的是，具有ESR1突变的细胞也可以上调AR，证明了这些突变与AR之间的独特关系。我们的目标是：（1）确定是否受体串扰（WT或AR突变体）是对激素剂的抗性机制，（2）对确定AR是否采用新型的核受体相互作用来驱动激素耐药性，（3）确定AR和ESR1突变对侵袭和转移的影响。关键的成功已在开发具有内源性的AR与获得的抗性相一致的抗性模型，我们已经确定了潜在的AR介导的候选抗性机制。无疑是激素患者的耐药性是多因素的，需要组合激素和靶向治疗以及了解关键途径的激活状态的知识，例如由ER中的突变引起转移性肿瘤。我们的工作将影响许多复发性ER阳性乳腺癌的女性抗治疗疾病。