The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers
The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers
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DOI：
10.1172/jci30866
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发表时间：
2007-05-01
影响因子：
15.9
通讯作者：
Ellisen, Leif W.
中科院分区：
文献类型：
--
作者：
Leong, Chee-Onn;Vidnovic, Nick;Ellisen, Leif W.
缺乏雌激素和孕激素受体表达和HER 2扩增的乳腺癌表现出不同的基因表达谱和临床特征，它们构成了大多数BRCA 1相关肿瘤。在这里，我们证明了p53家族成员p63控制p73依赖性顺铂敏感性特异性的途径，这些“三阴性”肿瘤。在体内，Delta Np 63和TAp 73亚型仅在通常表现出p53突变失活的三阴性原发性乳腺癌亚组中共表达。Delta Np 63 α亚型通过结合TAp 73从而抑制其促凋亡活性来促进乳腺癌细胞的存活。因此，通过RNA干扰抑制p63导致TAp 73依赖性诱导促凋亡Bcl-2家族成员和细胞凋亡。表达Delta Np 63 α和TAp 73的乳腺癌细胞表现出独特地依赖于TAp 73的顺铂敏感性。因此，作为对顺铂治疗的响应，而不是其他化疗剂，TAp 73经历了c-Abl依赖性磷酸化，这促进了Delta Np 63 α/TAp 73蛋白复合物的解离、促凋亡Bcl-2家族成员的TAp 73依赖性转录和凋亡。这些发现将p63定义为乳腺癌亚组中的生存因子;此外，它们提供了我们认为是这些三阴性癌症中顺铂敏感性的新机制，并且它们表明这些癌症可能具有BRCA 1相关肿瘤的顺铂敏感性。
Breast cancers lacking estrogen and progesterone receptor expression and HER2 amplification exhibit distinct gene expression profiles and clinical features, and they comprise the majority of BRCA1-associated tumors. Here we demonstrated that the p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity specific to these "triple-negative" tumors. In vivo, Delta Np63 and TAp73 isoforms were coexpressed exclusively within a subset of triple-negative primary breast cancers that commonly exhibited mutational inactivation of p53. The Delta Np63 alpha isoform promoted survival of breast cancer cells by binding TAp73 and thereby inhibiting its proapoptotic activity. Consequently, inhibition of p63 by RNA interference led to TAp73-dependent induction of proapoptotic Bcl-2 family members and apoptosis. Breast cancer cells expressing Delta Np63 alpha and TAp73 exhibited cisplatin sensitivity that was uniquely dependent on TAp73. Thus, in response to treatment with cisplatin, but not other chemotherapeutic agents, TAp73 underwent c-Abl-dependent phosphorylation, which promoted dissociation of the Delta Np63 alpha/TAp73 protein complex, TAp73-dependent transcription of proapoptotic Bcl-2 family members, and apoptosis. These findings define p63 as a survival factor in a subset of breast cancers; furthermore, they provide what we believe to be a novel mechanism for cisplatin sensitivity in these triple-negative cancers, and they suggest that such cancers may share the cisplatin sensitivity of BRCA1-associated tumors.