Targeting Posttranslational Modifications in Breast Carcinogenesis

乳腺癌中的靶向翻译后修饰 三阴性乳腺癌（TNBC）预后不良，不适合内分泌或HER 2- 靶向治疗。虽然新批准的PARP抑制剂（PARPi），如奥拉帕尼和塔拉唑帕尼， 这给大约15-20%的BRCA 1缺陷的TNBC患者带来了一线希望，需要一种新的治疗方法。 因此，制定一项能够使剩余的80-85% BRCA 1-熟练的TNBC患者受益的策略是紧迫和重要的。的 本项目的目标是确定Krüppel样因子4（KLF 4）和聚ADP之间相互作用的影响， 核糖聚合酶1（PARP 1）在乳腺肿瘤的进展和转移中的作用，并进一步发展为小分子 KLF 4抑制剂，其与PARPi协同用于抗TNBC治疗。这一建议是基于我们原来的 发现KLF 4在介导DNA损伤反应（DDR）/DNA修复中充当关键信号节点， 其中PARP 1对KLF 4的聚（ADP-核糖基）化（PAR化）决定了KLF 4的染色质募集 这反过来又控制KLF 4转录功能，以维持基因组的稳定性，肿瘤 乳腺癌的进展/转移和药物敏感性。这些发现引出了我们的核心假设， PARP 1对KLF 4的失调导致基因组不稳定，肿瘤促进进展/转移， 通过新开发的KLF 4抑制剂阻断KLF 4协同PARPi有效杀死TNBC细胞。三 具体目标是阐明PARP 1调控KLF 4的重要性和机制：（1） 确定PARP 1调节KLF 4介导的基因组稳定性和致癌作用的机制 通过协调KLF 4向染色质的募集;（2）确定KLF 4在细胞内的生理和临床表达， KLF 4 PAR化在乳腺肿瘤进展/转移中的相关性;以及（3）验证治疗性KLF 4 PAR化的方法。 KLF 4抑制剂在使用人乳腺抗TNBC治疗中与奥拉帕尼/talazoparib协同作用的干预 肿瘤类器官和患者来源的异种移植物（PDX）。 ! ! !

Targeting Posttranslational Modifications in Breast Cancer Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2- targeted therapies. While the newly approved PARP inhibitors (PARPi) such as olaparib and talazoparib provide a glint of hope to the approximately 15-20% of TNBC patients with BRCA1-deficiency, the need for a novel strategy that could benefit the remaining 80-85% BRCA1-proficient TNBC patients is urgent and significant. The goal of this project is to determine the impact of interplay between Krüppel-like factor 4 (KLF4) and poly-ADP- ribose polymerase 1 (PARP1) in breast tumor progression and metastasis, and further develop a small molecule inhibitor of KLF4 that synergizes with PARPi for anti-TNBC treatment. This proposal is based on our original discovery that KLF4 acts as a critical signaling node in mediating DNA damage response (DDR)/DNA repair, wherein the Poly-(ADP-ribosyl)ation (PARylation) of KLF4 by PARP1 dictates the chromatin recruitment for KLF4 that, in turn, governs KLF4 transcriptional function with respect to the maintenance of genome stability, tumor progression/metastasis and drug sensitivity in breast cancer. These findings led to our central hypothesis that dysregulation of KLF4 by PARP1 results in genome instability and tumor promotes progression/metastasis, and blockade of KLF4 by newly developed KLF4 inhibitor synergizes PARPi for efficient killing of TNBC cells. Three specific aims are proposed to elucidate the importance and mechanisms regulating KLF4 by PARP1: (1) To determine the mechanism by which PARP1 regulates KLF4-mediated genome stability and carcinogenesis through orchestrating the recruitment of KLF4 to chromatin; (2) To determine the physiological and clinical relevance of KLF4 PARylation in breast tumor progression/metastasis; and (3) To validate the therapeutic intervention of KLF4 inhibitor in synergizing with olaparib/talazoparib in anti-TNBC treatment using human breast tumor organoid and patient-derived xenografts (PDXs). ! ! !