The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression
The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression
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DOI：
10.1073/pnas.0711032105
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发表时间：
2008-05-13
影响因子：
11.1
通讯作者：
Ludwig, Thomas
中科院分区：
文献类型：
--
作者：
Shakya, Reena;Szabolcs, Matthias;Ludwig, Thomas
携带BRCA1肿瘤抑制基因种系突变的女性易患乳腺癌和卵巢癌。BRCA1的蛋白产物参与了广泛的生物过程，并与许多不同的蛋白相互作用。其中之一，BARD1，与BRCA1结合形成异二聚体复合物，作为泛素E3连接酶具有酶活性。尽管BRCA1/BARD1异源二聚体与BRCA1功能的几个方面有关，但其在肿瘤抑制中的作用尚未得到评估。为了解决这个问题，我们产生了携带Bard1或Brca1条件等位基因的小鼠菌株，并使用Cre重组来灭活乳腺上皮细胞中的这些基因。值得注意的是，条件Bard1-和brca1突变小鼠发生的乳腺癌在频率、潜伏期、组织病理学和细胞遗传学特征方面彼此（以及与双重条件Bard1/ brca1突变动物）无法区分。与人类BRCA1突变携带者的基底样乳腺癌类似，这些肿瘤在雌激素和孕激素受体表达和HER2/neu扩增方面呈“三阴性”。它们也表达基础细胞角蛋白CK5和CK14， p53病变频率升高，并表现出高水平的染色体不稳定性。Bard1-、Brcal-和Bard1/ BRCA1突变小鼠乳腺癌的显著相似性表明，这两个基因的抑瘤活性都是通过BRCA1/ Bard1异源二聚体介导的。
Women with germ-line mutations of the BRCA1 tumor suppressor gene are highly susceptible to breast and ovarian cancer. The protein product of BRCA1 is involved in a broad spectrum of biological processes and interacts with many diverse proteins. One of these, BARD1, associates with BRCA1 to form a heterodimeric complex that is enzymatically active as an ubiquitin E3 ligase. Although the BRCA1/BARD1 heterodimer has been implicated in several aspects of BRCA1 function, its role in tumor suppression has not been evaluated. To address this question, we generated mouse strains carrying conditional alleles of either Bard1 or Brca1 and used Cre recombination to inactivate these genes in mammary epithelial cells. Significantly, the conditional Bard1- and Brca1-mutant mice developed breast carcinomas that are indistinguishable from each other (and from those of double conditional Bard1/Brca1-mutant animals) with respect to their frequency, latency, histopathology, and cytogenetic features. Reminiscent of the basal-like breast carcinomas seen in human BRCA1 mutation carriers, these tumors are "triple negative" for estrogen and progesterone receptor expression and HER2/neu amplification. They also express basal cytokeratins CK5 and CK14, have an elevated frequency of p53 lesions, and display high levels of chromosomal instability. The remarkable similarities between the mammary carcinomas of Bard1-, Brcal-, and Bard1/Brca1-mutant mice indicate that the tumor suppressor activities of both genes are mediated through the BRCA1/BARD1 heterodimer.