A precision medicine basis for estrogen therapy for advanced breast cancer

项目摘要：一些雌激素受体α(ER)阳性乳腺癌的原因尚不清楚 对雌激素治疗敏感而其他药物耐药，以及有效利用雌激素治疗的策略 都不是很成熟。这项研究的长期目标是最大限度地发挥临床潜力 雌激素受体阳性乳腺癌的内分泌治疗。该项目的总体目标是定义 雌激素17b-雌二醇影响ER+乳腺癌细胞命运的机制。这个 中心假说是雌激素非依赖性的基础转录活性是由ER扩增引起的， 过表达或突变使乳腺癌细胞对17b-雌二醇/雌激素受体诱导的细胞毒作用敏感 DNA损伤。这一项目理由是：(1)治疗的机制 对17b-雌二醇的反应和(Ii)决定对17b-雌二醇反应的肿瘤特征将提供精确度 为其使用提供医学基础，并提供加强反应的策略。核心假设将通过以下方式进行检验 追求三个具体目标：(1)确定17b-雌二醇/内质网如何引起DNA损伤和反应控制 细胞命运；(2)确定DNA损伤反应的抑制如何影响对17b-雌二醇的敏感性；(3) 明确ER(ESR1)突变在决定乳腺癌对17b-雌二醇反应中的作用。第一个目标是， 17b-雌二醇/内质网诱导转录活性、DNA损伤、 并将在基因工程和雌激素非依赖性ER+乳腺癌细胞中测量反应。 这些研究将为17b-雌二醇的细胞毒性作用提供机制基础。第二个目标是 使用细胞系和患者来源的异种移植物来测量17b-雌二醇在血管内皮细胞瘤中的作用 聚腺苷二磷酸核糖聚合酶1/2(PARP)的药理抑制及其同源重组 缺乏症。这些研究将提供治疗策略，以增强对17b-雌二醇的反应。在第三个目标中， 工程细胞和ESR1突变患者来源的异种移植物将用于测量17b-雌二醇- 诱导细胞命运、肿瘤生长和ER转录活性的变化。这些研究将提供 了解ESR1突变如何影响癌细胞对17b-雌二醇的反应并提供一种机制 以告知其临床使用情况。这项拟议的研究具有创新性，因为它涉及内质网诱导的DNA 17b-雌二醇诱导的细胞毒性机制的损伤，使其能够发展为 针对晚期ER+乳腺癌DNA损伤反应的策略。根据我们的临床试验 发现，该项目将测试ER突变使ER+乳腺癌细胞对 17B-雌二醇。这项拟议的研究意义重大，因为它将揭示17b-雌二醇的根本原因-- 在ER+乳腺癌中诱导的细胞毒性，以及解释细胞适应如何将17b-雌二醇从 从生长促进剂到生长抑制剂。这项研究也将为临床提供强有力的科学依据。 17b-雌二醇治疗在可遗传识别的患者亚群中的测试。

Project Summary: It remains unknown why some estrogen receptor alpha (ER)-positive breast cancers are sensitive to estrogen therapy while others are resistant, and strategies for effectively utilizing estrogen therapy are not well-established. The long-term goal of this line of investigation is to maximize the clinical potential of endocrine therapies for the management of ER+ breast cancer. The overall objective of this project is to define the mechanism that controls cell fate in ER+ breast cancer in response to the estrogen 17b-estradiol. The central hypothesis is that basal estrogen-independent ER transcriptional activity caused by ER amplification, overexpression, or mutation sensitizes breast cancer cells to the cytotoxic effects of 17b-estradiol/ER-induced DNA damage. The rationale for this project is that definition of (i) the mechanism underlying therapeutic response to 17b-estradiol and (ii) tumor features that dictate response to 17b-estradiol will provide a precision medicine basis for its use and offer strategies to enhance response. The central hypothesis will be tested by pursuing three specific aims: (1) Determine how 17b-estradiol/ER-induced DNA damage and response control cell fate; (2) Determine how inhibition of the DNA damage response affects sensitivity to 17b-estradiol; (3) Define the role of ER (ESR1) mutations in dictating breast cancer response to 17b-estradiol. In the first aim, the kinetics and spatiotemporal relationship of 17b-estradiol/ER-induced transcriptional activity, DNA damage, and response will be measured in genetically engineered and estrogen-independent ER+ breast cancer cells. These studies will provide a mechanistic basis for the cytotoxic effects of 17b-estradiol. The second aim will use cell lines and patient-derived xenografts for measurement of the effects of 17b-estradiol in the context of pharmacological inhibition of poly(ADP-ribose) polymerases 1/2 (PARP) as well as homologous recombination deficiency. These studies will offer treatment strategies to enhance response to 17b-estradiol. In the third aim, engineered cells and ESR1-mutant patient-derived xenografts will be used for measurement of 17b-estradiol- induced changes in cell fate, tumor growth, and ER transcriptional activity. These studies will provide understanding of how ESR1 mutations shape cancer cell response to 17b-estradiol and provide a mechanistic basis to inform its clinical use. The proposed research is innovative because it implicates ER-induced DNA damage in the mechanism of cytotoxicity induced by 17b-estradiol therapy, enabling the development of strategies that target the DNA damage response for advanced ER+ breast cancer. Based on our clinical trial findings, this project will test the innovative concept that ER mutations sensitize ER+ breast cancer cells to 17b-estradiol. The proposed research is significant because it will reveal the root cause of 17b-estradiol- induced cytotoxicity in ER+ breast cancer, as well as explain how cell adaptations convert 17b-estradiol from a growth promoter to a growth suppressor. This research will also provide strong scientific rationale for clinical testing of 17b-estradiol therapy in genetically identifiable patient subpopulations.