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首页> 外文期刊>EBioMedicine >CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target
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CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target

机译：CPSF6是与临床相关的乳腺癌易感性目标

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Breast cancer represents a major health challenge. The majority of breast cancer deaths are due to cancer progression/recurrence for which no efficient therapies exist. Aggressive breast cancers are characterized by loss of cellular differentiation. Defining molecular mechanisms/targets contributing to cancer aggressiveness is needed to guide the design of new screening and targeted treatments. Here, we describe a novel tumor promoting function for the Cleavage and Polyadenylation Factor-6 (CPSF6). Importantly, aggressive breast cancer cells of luminal B, HER2-overexpressing and triple negative subtypes show dependency on CPSF6 for viability and tumorigenic capacity. Mechanistically, we found CPSF6 to interact with components of the A-to-I RNA editing machinery, paraspeckles and ADAR1 enzyme, and to be required for their physical integrity. Clinically, we found CPSF6 and all core paraspeckles proteins to be overexpressed in human breast cancer cases and their expression to correlate with poor patient outcomes. Finally, we found prolactin, a key mammary differentiation factor, to suppress CPSF6/RNA editing activity. Together, this study revealed CPSF6 as a molecular target with clinical relevance for prognosis and therapy in breast cancer.
机译：乳腺癌是一项重大的健康挑战。大多数乳腺癌死亡是由于癌症进展/复发而导致的，目前尚无有效的治疗方法。侵略性乳腺癌的特征在于细胞分化的丧失。需要确定有助于癌症侵袭性的分子机制/靶标，以指导新筛查和靶向治疗的设计。在这里，我们描述了一种新的肿瘤促进功能的分裂和聚腺苷酸化因子6（CPSF6）。重要的是，腔B，过度表达HER2和三阴性的亚型的侵袭性乳腺癌细胞显示出对CPSF6的生存能力和致瘤能力的依赖性。从机制上讲，我们发现CPSF6与A-to-I RNA编辑机器，副斑点和ADAR1酶的成分相互作用，并且是它们物理完整性所必需的。在临床上，我们发现CPSF6和所有核心散斑蛋白在人类乳腺癌病例中过表达，它们的表达与不良患者预后相关。最后，我们发现催乳素是一种关键的乳腺分化因子，可抑制CPSF6 / RNA编辑活性。总之，这项研究表明CPSF6是一种分子靶标，与乳腺癌的预后和治疗具有临床相关性。

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