BLC (Basal-like breast cancers) 是高恶变的肿瘤形式，且预后情形差，约占人类乳癌病例的 15%。偶发性BLC 与多数乳癌患者，都具有BRCA1 （一种乳腺癌抑制基因）突变，其雌激素受体都没有表达，并且没有过量制造 HER2 蛋白。因此针对雌激素受体或HER2 等常用的乳癌疗法并不适用。Dana-Farber癌症学院、Brigham 和妇女医院等地的研究人员则发现，X 染色体异常与BRCA1 正常的偶发性 BLC以及遗传性 BRCA1 变异乳腺癌有关。这篇文章发表在最近的Cancer Cell上。
BRCA1 缺陷已知与女性性染色体稳定机制有关。通常女性体内的两条X染色体会在胚胎阶段经 X 失活过程使得其中一条 X 染色体 (Xi) 不会表达。先前研究发现 BRCA1 具变异的乳腺癌病例会有 Xi 缺失的现象。此研究中，Andrea Richardson 博士等人则针对偶发性 BLC 异常表达与 Xi 染色体管理的关联进行分析。
结果发现，许多偶发性 BLC 都有 Xi 缺失的情形。这些肿瘤也有X 染色体上特定基因表达增加的情况。所分析的 BLC BRCA1 基因正常，表明其它与细胞路径有关的基因出现异常。研究人员表示，这项分析发现偶发性和与 BRCA1
有关的乳癌新致病机制。而更深入地了解两个活化的 X 染色体与癌症发展的关联性，将有助于乳腺癌新疗法的研发。
原文：
Basal-like breast cancers (BLC) are highly aggressive tumors with a relatively poor prognosis that account for approximately 15% of sporadic human breast cancer. Sporadic BLC share certain characteristics with most of the breast cancers from patients carrying a germline mutation in the BRCA1 breast cancer suppressor gene. Among their similarities, sporadic BLC and BRCA1 cancers do not express the estrogen receptor and do not overproduce HER2 protein. Thus, therapeutics targeting estrogen receptor or targeting HER2 currently used in treating some other types of breast cancers are unlikely to be useful for treating these breast cancers. However, sporadic BLC contain normal BRCA1 genes. A new study published in the February issue of Cancer Cell provides evidence that X chromosome abnormalities contribute to the pathogenesis of both the sporadic BRCA1 normal BLC and the inherited BRCA1 mutant breast cancer.
Defects in the BRCA1 gene have been linked to an abnormality in a mechanism that contributes to the stability of sex chromosomes in women. In mammals, male cells contain an X and a Y chromosome, while female cells contain two X chromosomes. Normally, a process called X inactivation occurs in early female embryos; it leads to silencing of one of the two X chromosomes in derivative embryonic and adult somatic cells. The authors had previously shown that loss of the inactive X chromosome (Xi) occurs in BRCA1 mutation-carrying breast cancers. Given the similarities between BRCA1-associated cancer and sporadic BLC, Drs. Andrea Richardson, Zhigang Wang, Dirk Iglehart, David M. Livingston, and Shridar Ganesan, and colleagues from the Dana-Farber Cancer Institute and Brigham and Women's Hospital, examined whether sporadic BLC display abnormalities in the management of the Xi chromosome.
The researchers found that, like BRCA1-associated cancers, most sporadic BLC have consistently lost the Xi and displayed a higher than normal number of apparently active X chromosomes These tumors also showed increased expression of a small, but specific, subset of X chromosomal genes. Interestingly, since all sporadic BLC analyzed displayed normal BRCA1 genes and gene expression, it was hypothesized that BLC have acquired defects in genes other than BRCA1 that contribute to some of the same cellular pathways as those that are defective in BRCA1-associated cancers. One wonders whether one or more of these pathways support(s) the maintenance of a normal Xi. "These results provide new insight into possible pathogenic mechanisms underlying both sporadic and BRCA1-associated basal-like breast cancer," explain the authors. Ideally, a better understanding of how two active X chromosomes are associated with cancer development and progression could lead to new insights into rational treatment strategies for these subtypes of breast cancer.
###
The researchers include Andrea L. Richardson, Zhigang C. Wang, and Alexander Miron of Brigham and Women's Hospital and Harvard Medical School in Boston, MA; Arcangela De Nicolo of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA and the University of Padua in Padua, Italy; Xin Lu of the Harvard School of Public Health in Boston, MA; Myles Brown, Xiaodong Liao, and David M. Livingston of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA; Shridar Ganesan of the Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA and UMDNJ-Robert Wood Johnson School of Medicine in New Brunswick, NJ; J. Dirk Iglehart of Brigham and Women's Hospital, Harvard Medical School, and the Dana-Farber Cancer Institute in Boston, MA. This work was supported by a generous gift in support of cancer research from Deborah and Robert First. It was also supported by the Dana-Farber/Harvard SPORE in Breast Cancer, by other grants from the National Cancer Institute, and by the Breast Cancer Research Foundation.
Richardson et al.: "X chromosomal abnormalities in basal-like, human breast cancer." Publishing in Cancer Cell 9, 121–132, February 2006. DOI 10.1016/j.ccr.2006.01.013 http://www.cancercell.org/
