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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：
10113551
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113551
关键词：
Adjuvant Therapy Affect Androgen Receptor Androgens Aromatase Inhibitors Breast Cancer Model Breast Cancer Patient Breast cancer metastasis Candidate Disease Gene Cells Clinical Collaborations 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 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 silico in vivo innovation malignant breast neoplasm metastatic process migration mutant non-genomic novel novel strategies novel therapeutic intervention overexpression predictive marker pressure prognostic promoter receptor refractory cancer 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）阳性的乳腺肿瘤是用内分泌疗法治疗的