Division of Breast and Endocrine Surgery, St, Marianna University School of Medicine, Kawasaki, 216-8511, Japan.
Cell Div. 2008 Jan 7;3:1. doi: 10.1186/1747-1028-3-1.
The basal-like breast cancer, a new category of breast cancer associated with poor prognosis and possibly unique chemosensitivity, is a current topic in the breast cancer field. Evidence from multiple sources strongly indicate that impairment of BRCA1 pathways is responsible for this phenotype, implying the importance of BRCA1 not only in familial breast cancers but also in sporadic cancers. BRCA1 acts as a hub protein that coordinates a diverse range of cellular pathways to maintain genomic stability. BRCA1 participates in multiple cellular supercomplexes to execute its tasks and, in most of the complexes, BRCA1 exists as a RING heterodimer with BARD1 to provide ubiquitin E3 ligase activity that is required for its tumor suppressor function. It was revealed recently that the BRCA1 RING finger is capable of catalyzing multiple types of ubiquitination depending upon the interacting E2, the ubiquitin carrier protein. BRCA1 may catalyze distinct ubiquitination on different substrates as the situation demands. On the other hand, in response to DNA double-strand breaks where BRCA1 plays its major role for homologous recombination repair, recent evidence showed that ubiquitination is a critical step to recruit BRCA1 to the damaged site through UIM (ubiquitin interacting motif) containing protein RAP80. Thus, ubiquitin and BRCA1 likely affect each other in many ways to perform cellular functions. Elucidation of this mechanism in relation to cell survival is now much anticipated because it could be a key to predict chemosensitivity of basal-like breast cancer.
基底样乳腺癌是一种与预后不良相关的新型乳腺癌，可能具有独特的化疗敏感性，是当前乳腺癌领域的一个热门话题。来自多个来源的证据强烈表明，BRCA1 途径的损伤是导致这种表型的原因，这意味着 BRCA1 不仅在家族性乳腺癌中很重要，而且在散发性癌症中也很重要。BRCA1 作为一种枢纽蛋白，协调多种细胞途径以维持基因组稳定性。BRCA1 参与多个细胞超复合物来执行其任务，在大多数复合物中，BRCA1 与 BARD1 形成 RING 异二聚体，提供泛素 E3 连接酶活性，这是其肿瘤抑制功能所必需的。最近的研究表明，BRCA1 的 RING 指状结构能够根据相互作用的 E2（泛素载体蛋白）催化多种类型的泛素化。BRCA1 可能根据需要在不同的底物上催化不同的泛素化。另一方面，在 BRCA1 发挥其主要作用的 DNA 双链断裂处，用于同源重组修复，最近的证据表明，泛素化是通过含有 UIM（泛素相互作用基序）的蛋白 RAP80 将 BRCA1 招募到损伤部位的关键步骤。因此，泛素和 BRCA1 可能以多种方式相互影响，以发挥细胞功能。阐明与细胞存活相关的这种机制现在备受期待，因为它可能是预测基底样乳腺癌化疗敏感性的关键。
