Targeting Oncogenic PELP1/SRC-3 Signaling Complexes in ER+ Breast Cancer

项目摘要 乳腺癌是女性最常见的诊断癌症，雌激素受体阳性(ER+)的乳房 癌症占病例的75%。针对阻断ER作用的内分泌治疗是非常有效的； 然而，40%患有ER+肿瘤的女性对转移性疾病产生抵抗力并取得进展。ER+肿瘤 复发晚了，肿瘤细胞可以保持几年到几十年的静止状态。转移性肿瘤的治疗进展 乳腺癌受到主要针对快速增殖的肿瘤细胞的策略的限制。促成因素 晚期疾病进展包括乳腺癌干细胞(CSC)，这种细胞增殖能力差，存在 作为治疗耐药肿瘤中的少数群体。我们鉴定为SRC-3(类固醇受体[SR]共激活因子3) 作为PELP1的一个新的细胞质结合伙伴。与SRC-3类似，PELP1是一个内质网共激活因子，并且 在细胞核和细胞质之间动态穿梭，充当核共激活物和细胞质 生长因子和类固醇受体的支架蛋白。PELP1在正常乳腺中主要是有核的，但 PELP1胞浆定位增加是一种致癌事件，通过以下方式促进疾病进展 未知的机制。我们发现PELP1/SRC-3细胞质复合体驱动乳腺CSC表型和 ER+乳腺癌模型中与促生存相关的基因。SRC-3抑制作用破坏复合体的形成 和细胞质PELP1诱导的肿瘤球体。从rna-seq分析中确定的最佳候选对象包括 PFKFB家族成员，它们是双功能的激酶/磷酸酶，在癌症新陈代谢和 CSC生物学。PFKFB3/-4与PELP1/SRC-3复合物共纯化；阻断对PFKFB3/-4的抑制 PELP1/SRC-3复合体的形成与生物学值得注意的是，PELP1/SRC-3 CSC生物学被发现 他莫昔芬耐药(TamR)和紫杉醇耐药(TaxR)模型。在此，我们假设PELP1/SRC-3 复合体放大PFKFB家族成员的信号输入，介导所需的代谢途径改变 对于耐药的ER+肿瘤细胞群。我们将：1)确定PELP1/SRC-3所必需的信号通路 2)确定靶向治疗的益处 PELP1/SRC-3/PFKFB复合体体内阻断肿瘤进展和转移的研究我们的长期目标 确定可作为消除治疗的组合策略的非ER治疗靶点 ER+乳腺癌中的耐药肿瘤细胞。在K22奖期间，我们希望定义分子连接 乳腺癌进展、转移和检查中癌细胞代谢和致癌事件之间的关系 靶向这一通路以减少晚期复发的好处。这项提议将为 这位候选人在向独立过渡期间转向转化型癌症研究的目标。 确定主要参与者将从根本上重新定义针对耐药治疗的标准护理选项 ER+乳腺癌的人群。

Project Summary Breast cancer is the most commonly diagnosed cancer in women, with estrogen receptor positive (ER+) breast cancers accounting for 75% of cases. Endocrine therapies directed at blocking ER action are highly effective; however, 40% of women with ER+ tumors develop resistance and progress to metastatic disease. ER+ tumors relapse late, and tumor cells can remain quiescent for years to decades. Progress in the treatment of metastatic breast cancer is limited by strategies that primarily target rapidly proliferating tumor cells. Contributing factors to advanced disease progression include breast cancer stem cells (CSC), which are poorly proliferative and exist as minority populations in therapy resistant tumors. We identified SRC-3 (steroid receptor [SR] co-activator 3) as a novel cytoplasmic binding partner of PELP1. Similar to SRC-3, PELP1 is an ER co-activator, and dynamically shuttles between the nucleus and cytoplasm to act as a nuclear co-activator and cytoplasmic scaffolding protein for growth factor and steroid receptors. PELP1 is primarily nuclear in normal breast, but increased cytoplasmic localization of PELP1 is an oncogenic event that promotes disease progression by unknown mechanisms. We showed PELP1/SRC-3 cytoplasmic complexes drive breast CSC phenotypes and genes associated with pro-survival in ER+ breast cancer models. SRC-3 inhibition disrupts complex formation and cytoplasmic PELP1-induced tumorspheres. Top candidates identified from RNA-seq analysis include PFKFB family members, which are bi-functional kinase/phosphatases that have roles in cancer metabolism and CSC biology. PFKFB3/-4 co-purified with PELP1/SRC-3 complexes; inhibition of PFKFB3/-4 blocked PELP1/SRC-3 complex formation and biology. Remarkably, PELP1/SRC-3 CSC biology is phenocopied in tamoxifen-resistant (TamR) and paclitaxel-resistant (TaxR) models. Herein, we hypothesize that PELP1/SRC-3 complexes amplify signaling inputs to PFKFB family members that mediate altered metabolic pathways required for resistant ER+ tumor cell populations. We will: 1) identify signaling pathways essential for PELP1/SRC-3 driven therapy resistance using mass cytometry, and 2) determine the therapeutic benefits of targeting PELP1/SRC-3/PFKFB complexes in vivo to block cancer progression and metastasis. Our long-term objectives are to identify non-ER therapeutic targets that can be developed as combination strategies to eliminate therapy resistant tumor cells in ER+ breast cancer. During the K22 award, we expect to define the molecular links between cancer cell metabolism and oncogenic events in breast cancer progression, metastasis, and examine the benefits of targeting this pathway to impair late recurrence. This proposal will provide a solid foundation for the candidate’s goal of moving towards translational cancer research during her transition to independence. Delineating the key players will fundamentally redefine standard care options to target therapy-resistant populations in ER+ breast cancer.