PELP1 mislocalization favors hormone-induced breast cancer development

项目摘要 雌激素受体（ER）阳性的管腔型乳腺癌占近75%的病例，并经常含有 广泛的孕激素受体（PR）阳性细胞。虽然内分泌疗法针对阻断ER 这些措施非常有效，高达1/3的患者最终进展为转移性疾病。ER和PR是关键 旁分泌（即细胞之间）信号事件的介质。我们预测旁分泌信号是对 异常的类固醇激素受体（SR）作用深刻地影响乳腺肿瘤的进展，部分原因是 调节肿瘤周围的局部环境。一种新兴的生物标志物， 浸润性ER+乳腺癌患者的乳腺癌风险和预后不良是细胞质（细胞-） PELP 1，正常核SR辅激活剂。Cyto-PELP 1通过未知途径放大增殖信号通路 机制等我们的小组发现ER和PR-B在新的信号传导中与PELP 1合作， 转录复合物调节雌激素诱导的“PELP/ER/PR”靶基因的整体变化 表达与晚期肿瘤行为和内分泌抵抗相关。在此，我们假设 PELP 1向细胞质的穿梭/错误定位作为早期致癌事件起作用，其直接激活细胞质中的蛋白质。 信号通路输入到核ER和/或PR作用，导致改变的转录程序， 肿瘤诱导的肿瘤发展和快速进展。为了解决这个研究问题，我们的目标将 确定：1）细胞-PELP 1/ER/PR复合物作为改变的细胞驱动SR靶点的介导物的影响 基因表达，特别是调节微环境的酶诱导的旁分泌途径，2） 在由PELP 1动态引起的改变的SR作用中选择细胞PELP 1结合配偶体的要求 穿梭和错误定位到细胞质，以及3）细胞-PELP 1如何有助于细胞诱导的肿瘤 在体内形成和发展。这项研究计划将跨越现代分子，信号，表观遗传， 遗传技术，并采用互补的体外和体内模型。拟议的培训计划将 扩展申请人的技术和理论广度和深度，并与适当的专业知识相平衡， 合作者和指导，包括广泛的职业发展。总的来说，该提案将提供 申请人具有坚实的基础，可以过渡到未来专注于癌症研究的独立工作。在 短期内，该项目将产生更多的清晰度和洞察力，有关cyto的背景依赖性行动， 含PELP 1/ER/PR的复合物在调节ER+管腔型乳腺癌发展中的作用比如说 使用与细胞-PELP 1相关的新基因标记（本文开发）可能是一种有用的工具， 长期内分泌治疗复发风险高的患者，并揭示了旨在 预防乳腺癌的发展。

Project Summary Estrogen receptor (ER) positive luminal breast cancers account for nearly 75% of cases and frequently contain a wide range of progesterone receptor (PR) positive cells. While endocrine therapies directed at blocking ER action are highly effective, up to 1/3 of patients eventually progress to metastatic disease. ER and PR are key mediators of paracrine (i.e. between cells) signaling events. We predict paracrine signaling in response to aberrant steroid hormone receptor (SR) action profoundly impacts breast tumor progression, in part by modulation of the local environment surrounding a developing tumor. An emerging biomarker of increased breast cancer risk and poor prognosis in patients with invasive ER+ breast cancer is cytoplasmic (cyto-) PELP1, a normally nuclear SR co-activator. Cyto-PELP1 amplifies proliferative signaling pathways by unknown mechanisms. Our group discovered that ER and PR-B collaborate with PELP1 in novel signaling and transcriptional complexes to regulate global changes in estrogen-induced “PELP/ER/PR” target gene expression associated with advanced tumor behaviors and endocrine resistance. Herein, we hypothesize shuttling/mislocalization of PELP1 to the cytoplasm acts as an early oncogenic event that activates direct signaling pathway inputs to nuclear ER and/or PR action, leading to altered transcription programs that favor hormone-induced tumor development and rapid progression. To address this research question, our Aims will determine: 1) the impact of cyto-PELP1/ER/PR complexes as mediators of altered hormone-driven SR target gene expression, particularly of hormone-induced paracrine pathways modulating the microenvironment, 2) the requirement for select cyto-PELP1 binding partners in altered SR actions stemming from PELP1 dynamic shuttling and mislocalization to the cytoplasm, and 3) how cyto-PELP1 contributes to hormone-induced tumor formation and progression in vivo. This research plan will span modern molecular, signaling, epigenetic, and genetic techniques, and employ complementary in vitro and in vivo models. The proposed training plan will extend the applicant's technical and theoretical breadth and depth, and is balanced with appropriate expertise, collaborators, and mentoring that includes extensive career development. Overall, this proposal will provide the applicant with a solid foundation to transition into future independent work focused in cancer research. In the short-term, this project will yield increased clarity and insight regarding the context-dependent actions of cyto- PELP1/ER/PR-containing complexes in modulating ER+ luminal breast cancer development. For example, the use of novel gene signatures (developed herein) associated with cyto-PELP1 may be a useful tool to identify patients at high risk for recurrence while on long-term endocrine therapy, and reveal novel strategies aimed at preventing breast cancer development.