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

雌激素受体(ER)阳性的乳腺肿瘤可以通过内分泌疗法进行治疗，这种疗法针对的是 呃。患者可以保持多年的无病状态；然而，对治疗的抵抗力最终会产生， 而且大多数女性将遭受转移性癌症的复发。我们假设解开 雌激素受体阳性乳腺癌妇女的长期治疗重点是确定新的机制 使用转移性肿瘤耐药治疗的耐药性，其中肿瘤进化和克隆选择 发生了。我们发现雄激素受体(AR)是一个新的临床靶点，它在 耐药的转移性肿瘤。我们了解到，AR在功能上与ER合作，而抵抗 可能与激素治疗完全阻断雄激素和雌激素的失败有关 发信号。我们还发现，AR过表达的细胞在体内会发生转移。此外，我们 我们首次发现雌激素受体ESR1基因在转移性肿瘤中可以突变；获得 我们推测的激素非依赖性和内分泌治疗抵抗功能也将受到影响 通过非配体依赖的AR信号。重要的是，ESR1突变的细胞也上调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的突变体ER)是一种抵抗激素制剂的机制，(2) 确定AR是否使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突变在侵袭和转移中的作用。在以下方面取得了关键成功 发展内源性AR上调与获得性耐药一致的耐药模型 已经确定了潜在的AR介导的候选抗性机制。毫无疑问，荷尔蒙 患者的治疗耐药性是多因素的，需要激素和靶向联合治疗。 以及关键通路的激活状态的知识，例如由内质网突变引起的 转移性肿瘤。我们的工作将影响大量ER阳性乳腺癌复发的女性 患有无法治疗的疾病。

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.