Most patients with estrogen receptor alpha–positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast cancer cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and apoptosis pathways. In cell line–derived and patient-derived xenografts of both WT and MT ER+ breast cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast cancer. Significance: Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast cancer.

中文翻译：

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一流的 ER 核心调节因子 PELP1 抑制剂针对 ER+ 乳腺癌

大多数雌激素受体α阳性（ER+）乳腺癌患者最初对治疗有反应，但最终随着疾病进展而产生治疗耐药性。致癌 ER 共调节因子（包括脯氨酸、谷氨酸和富含亮氨酸的蛋白 1 (PELP1)）的过度表达与乳腺癌进展有关。缺乏抑制 PELP1 的小分子是一个重大的知识差距。在这里，我们使用酵母双杂交筛选，鉴定了 PELP1 (PIP) 的新型肽抑制剂。生化检测表明，其中一种肽 PIP1 直接与 PELP1 相互作用，阻断 PELP1 的致癌功能。PIP1 的计算模型揭示了对其活性有贡献的关键残基，并促进了 PELP1 小分子抑制剂 SMIP34 的开发，进一步分析证实SMIP34直接与PELP1结合。在乳腺癌细胞中，SMIP34 以剂量依赖性方式减少细胞生长。SMIP34 不仅能抑制野生型 (WT) 乳腺癌细胞的增殖，还能抑制突变型 (MT) ER+ 和耐药乳腺癌细胞的增殖，部分原因是通过蛋白酶体途径诱导 PELP1 降解。RNA 测序分析表明，SMIP34 治疗改变了与雌激素反应、细胞周期和细胞凋亡途径相关的基因表达。在 WT 和 MT ER+ 乳腺癌模型的细胞系来源和患者来源的异种移植物中，SMIP34 减少了增殖并显着抑制了肿瘤进展。总的来说，这些结果证明 SMIP34 是晚期乳腺癌中致癌 PELP1 信号传导的一流抑制剂。意义：