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

• 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
• 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

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）阳性乳腺肿瘤采用专门针对雌激素受体（ER）的内分泌疗法进行治疗 急诊室。患者可以多年保持无病状态；然而，最终会产生对治疗的抵抗力， 大多数女性都会遭受转移性癌症的复发。我们假设关键是 ER阳性乳腺癌女性的长期治疗重点是确定新机制 使用转移性肿瘤对治疗产生耐药性，其中肿瘤进化和克隆选择已发生耐药性 发生。我们将雄激素受体（AR）确定为新的临床靶点，该靶点在 耐药性、转移性肿瘤。我们了解到 AR 在功能上与 ER 协作，并且抵抗 可能与激素治疗未能完全阻断雄激素和雌激素有关 发信号。我们还发现 AR 过表达细胞在体内发生转移。此外，我们 率先发现雌激素受体ESR1基因在转移性肿瘤中可能发生突变；获取 我们假设激素非依赖性和内分泌治疗抵抗功能也会受到影响 通过不依赖配体的 AR 信号传导。重要的是，具有 ESR1 突变的细胞也会上调 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 或带有 AR 的突变 ER）是对激素药物产生耐药性的机制，(2) 确定 AR 是否利用新的核受体相互作用来驱动激素抵抗，以及 (3) 确定 AR 和 ESR1 突变体对侵袭和转移的影响。已取得关键成功 开发具有与获得性耐药一致的 AR 内源性上调的耐药模型，我们 已经确定了潜在的 AR 介导的候选耐药机制。毫无疑问是激素 患者的治疗抵抗是多因素的，需要结合激素和靶向治疗 以及对关键通路激活状态的了解，例如由 ER 突变引起的通路 转移性肿瘤。我们的工作将影响大量患有 ER 阳性乳腺癌且复发的女性 患有耐药性疾病。