CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target: Role of CPSF6 in Breast Cancer.
CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target: Role of CPSF6 in Breast Cancer.
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DOI：
10.1016/j.ebiom.2017.06.023
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发表时间：
2017-07
期刊：
影响因子：
11.1
通讯作者：
Ali S
中科院分区：
文献类型：
--
作者：
Binothman N;Hachim IY;Lebrun JJ;Ali S
乳腺癌是一项重大的健康挑战。大多数乳腺癌死亡是由于没有有效的治疗方法的癌症进展/复发。侵袭性乳腺癌的特征是细胞分化丧失。需要明确促进癌症侵袭性的分子机制/靶点，以指导新的筛选和靶向治疗的设计。在这里，我们描述了一种新的促肿瘤功能的切割和聚腺苷化因子-6 （CPSF6）。重要的是，侵袭性乳腺癌细胞的luminal B， her2过表达和三阴性亚型显示依赖于CPSF6的生存能力和致瘤能力。在机制上，我们发现CPSF6与A-to-I RNA编辑机制、paraspeckles和ADAR1酶的组分相互作用，并且是其物理完整性所必需的。在临床上，我们发现CPSF6和所有核心副斑蛋白在人类乳腺癌病例中过表达，并且它们的表达与患者预后不良相关。最后，我们发现催乳素，一个关键的乳腺分化因子，抑制CPSF6/RNA编辑活性。总之，本研究揭示了CPSF6作为一个与乳腺癌预后和治疗具有临床相关性的分子靶点。侵袭性乳腺癌细胞的生存和肿瘤发生需要CPSF6。CPSF6和旁斑核心蛋白与乳腺癌预后不良相关。催乳素激素重编程细胞，抑制CPSF6与副斑和ADAR1 （A-I RNA编辑机制）的相互作用。luminal B、her2富集型和基底（三阴性）亚型的乳腺肿瘤与分化差和侵袭性行为相关。确定影响肿瘤侵袭性的靶点可能为预后和治疗提供新的模式。这项研究证明了CPSF6在侵袭性乳腺癌细胞的存活和致瘤能力中起着关键作用。CPSF6对于A-to-I RNA编辑复合体、副斑和ADAR1酶的物理完整性是必需的。CPSF6和核心副斑蛋白是不良患者预后的生物标志物。此外，还发现催乳素激素抑制CPSF6的功能。本研究强调了CPSF6作为乳腺癌的治疗靶点。
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. Aggressive breast cancer cells require CPSF6 for viability and tumorigenesis. CPSF6 and paraspeckles core proteins are associated with poor outcome in breast cancer. Prolactin hormone reprograms cells to suppress CPSF6 interaction with paraspeckles and ADAR1, A-I RNA editing machinery. Breast tumors of luminal B, HER2-enriched, and basal (triple negative) subtypes are associated with poor differentiation and aggressive behavior. Defining targets contributing to cancer aggressiveness may offer new modalities for prognosis and therapy. This study demonstrated the critical role of CPSF6 for survival and tumorigenic capacity of aggressive breast cancer cells. CPSF6 is required for the physical integrity of the A-to-I RNA editing complex, paraspeckles and ADAR1 enzyme. CPSF6 and core paraspeckles proteins are biomarkers of poor patient outcome. In addition, prolactin hormone was found to suppress CPSF6 function. This study highlights CPSF6 as a therapeutic target in breast cancer.
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影响因子：
4.6
作者：
López-Ozuna VM;Hachim IY;Hachim MY;Lebrun JJ;Ali S
通讯作者：
Ali S
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14.9
作者：
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Vagner S
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MIELE, A;BANDERA, M;GOLDSTEIN, BP
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GOLDSTEIN, BP
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作者：
Prasanth, KV;Prasanth, SG;Spector, DL
通讯作者：
Spector, DL