Targeting Mechanisms of Endocrine Resistance in Breast Cancer

项目摘要/摘要 抑制雌激素受体(ER)信号转导的内分泌治疗是系统性治疗的主要手段。 呃+乳腺癌。这些疗法包括降低雌激素水平的方法，包括黄体化 绝经前妇女的激素释放激素激动剂和芳香酶抑制剂 绝经后妇女，以及直接雌激素受体拮抗剂，如他莫昔芬和富维斯特朗。在晚期疾病中 然而，在这种情况下，内分泌治疗抵抗的癌症几乎总是出现，并且是 乳腺癌死亡人数。已经提出了多种遗传和表观遗传机制来解释 出现内分泌治疗抵抗。包括我们自己在内的几个小组已经表征了 在大约20-30%的病例中，ER基因(ESR1)本身是一种抗性机制。我们已经开发出 内分泌治疗耐药ER+乳腺癌的细胞系和患者来源的异种移植模型 这些ESR1突变，并发现这些突变表现出与配体无关的功能，模仿 雌激素结合的野生型内质网以及等位基因特异性的新形态特性与内质网新信号的关系 促进转移性EMT样表型的功能。此外，使用全基因组CRISPR筛查， 我们已经确定了ER+乳腺癌生长所必需的基因。重要的是，我们还确定了 在野生型ER环境中丢失导致内分泌治疗抵抗的基因，包括NF1，TSC1/2， PTEN和CSK。在这些研究中，我们发现CSK的丢失会导致SRC家族激酶的激活 (SFK)，从而促进雌激素非依赖性生长和支持转移的癌细胞表型。值得注意的是， 雌激素通过直接与转录增强子结合来调节CSK的表达 CSK基因。这揭示了雌激素诱导的抑制生长的负反馈回路的存在。 ER+肿瘤，从而限制了目前针对ER的治疗的疗效。这种反馈的存在 Loop提出了一种挑衅性的假设，即当前的内分泌治疗本身可能会促进一种亲- 转移表型。与本计划的主旋律保持一致，以定义新的治疗方法 脆弱性，我们将研究遗传和表观遗传异质性如何影响对 内分泌治疗。该项目的成功将使 内分泌治疗抵抗的机制，包括肿瘤异质性的影响 用于预测有效的新治疗靶点，并将允许研究 内分泌治疗抵抗、内分泌治疗与转移。

Project Summary/Abstract Endocrine therapies that inhibit estrogen receptor (ER) signaling are the mainstay of the systemic treatment of ER+ breast cancers. These therapies consist of approaches to reduce estrogen levels including luteinizing hormone-releasing hormone (LHRH) agonists in premenopausal women and aromatase inhibitors (AI) in postmenopausal women, and direct ER antagonists such as tamoxifen and fulvestrant. In the advanced disease setting, however, endocrine therapy-resistant cancers almost invariably emerge and are the major cause of breast cancer deaths. Multiple genetic and epigenetic mechanisms have been proposed to explain the emergence of endocrine therapy resistance. Several groups including our own have characterized mutations in the ER gene (ESR1) itself as a mechanism of resistance in approximately 20-30% of cases. We have developed cell line and patient-derived xenograft (PDX) models of endocrine therapy-resistant ER+ breast cancer driven by these ESR1 mutations and have found that these mutations exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that confer on ER novel signaling functions that promote a pro-metastatic EMT-like phenotype. In addition, using genome-wide CRISPR screens, we have identified genes essential for the growth of ER+ breast cancers. Importantly, we have also identified genes whose loss confers endocrine therapy resistance in the setting of the wild-type ER, including NF1, TSC1/2, PTEN and CSK. In these studies, we have found that loss of CSK leads to activation of SRC-family kinases (SFK), thereby promoting estrogen-independent growth and a pro-metastatic cancer cell phenotype. Notably, expression of CSK is regulated by estrogen through binding of ER directly to a transcriptional enhancer in the CSK gene. This reveals the existence of an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors thereby limiting the efficacy of current therapies that target ER. The existence of this feedback loop suggests the provocative hypothesis that current endocrine therapies may themselves promote a pro- metastatic phenotype. Consistent with the overarching theme of this program to define new therapeutic vulnerabilities, we will study how genetic and epigenetic heterogeneity impact the development of resistance to endocrine therapy. Success of this project will allow the development integrative models of the mechanisms of endocrine therapy resistance that include the effect of tumor heterogeneity that can be used to predict effective new therapeutic targets and will allow the investigation of the link between endocrine therapy resistance, endocrine therapy and metastasis.