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

项目摘要 乳腺癌是女性中最常见的癌症，雌激素受体阳性（ER+）乳腺癌 癌症占病例的75%。针对阻断ER作用的内分泌疗法非常有效; 然而，40%的ER+肿瘤患者会产生耐药性并进展为转移性疾病。ER+肿瘤 复发较晚，并且肿瘤细胞可以保持静止数年至数十年。转移性肝癌的治疗进展 乳腺癌受到主要靶向快速增殖的肿瘤细胞的策略的限制。成因 晚期疾病进展包括乳腺癌干细胞（CSC），其增殖性差， 作为少数群体在治疗耐药肿瘤。我们鉴定了SRC-3（类固醇受体[SR]共激活因子3） 作为PELP 1的新型胞质结合伴侣。与SRC-3类似，PELP 1是ER共激活剂，并且 在细胞核和细胞质之间动态穿梭，作为细胞核共激活剂和细胞质 生长因子和类固醇受体的支架蛋白。PELP 1在正常乳腺中主要是细胞核，但 PELP 1的细胞质定位增加是一种致癌事件，其通过以下方式促进疾病进展： 未知的机制我们发现PELP 1/SRC-3胞质复合物驱动乳腺CSC表型， ER+乳腺癌模型中与促生存相关的基因。SRC-3抑制破坏复合物形成 和细胞质PELP 1诱导的肿瘤球。从RNA-seq分析中鉴定的最佳候选物包括 PFKFB家族成员，其是在癌症代谢中起作用的双功能激酶/磷酸酶， CSC生物学。PFKFB 3/-4与PELP 1/SRC-3复合物共纯化; PFKFB 3/-4的抑制被阻断 PELP 1/SRC-3复合物形成和生物学。值得注意的是，PELP 1/SRC-3 CSC生物学是表型模仿， 他莫昔芬耐药（TamR）和紫杉醇耐药（TaxR）模型。在此，我们假设PELP 1/SRC-3 复合物放大PFKFB家族成员的信号输入， 对于耐药ER+肿瘤细胞群体。我们将：1）确定PELP 1/SRC-3所必需的信号通路 使用质谱细胞术驱动治疗抗性，和2）确定靶向的治疗益处 PELP 1/SRC-3/PFKFB复合物在体内阻断癌症进展和转移。我们的长期目标 目的是确定非ER治疗靶点，这些靶点可以作为联合策略开发， ER+乳腺癌中的耐药肿瘤细胞。在K22奖期间，我们希望定义分子链 乳腺癌进展、转移和检查中癌细胞代谢与致癌事件之间的关系 靶向这一途径以减少晚期复发的益处。这一建议将为以下方面奠定坚实的基础： 候选人的目标是在她向独立过渡期间转向转化癌症研究。 描述关键参与者将从根本上重新定义标准护理选项，以针对治疗抵抗者。 ER+乳腺癌患者。

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.