BLC  (Basal-like  breast  cancers)  是高惡變的腫瘤形式,，且預(yù)后情形差，約占人類乳癌病例的  15%,。偶發(fā)性BLC  與多數(shù)乳癌患者,，都具有BRCA1 （一種乳腺癌抑制基因）突變，其雌激素受體都沒有表達(dá),，并且沒有過量制造  HER2  蛋白,。因此針對雌激素受體或HER2  等常用的乳癌療法并不適用。Dana-Farber癌癥學(xué)院,、Brigham    和婦女醫(yī)院等地的研究人員則發(fā)現(xiàn),，X  染色體異常與BRCA1  正常的偶發(fā)性  BLC以及遺傳性  BRCA1  變異乳腺癌有關(guān)。這篇文章發(fā)表在最近的Cancer Cell上,。  

        BRCA1  缺陷已知與女性性染色體穩(wěn)定機制有關(guān),。通常女性體內(nèi)的兩條X染色體會在胚胎階段經(jīng)  X  失活過程使得其中一條  X  染色體  (Xi)  不會表達(dá)。先前研究發(fā)現(xiàn)  BRCA1  具變異的乳腺癌病例會有  Xi  缺失的現(xiàn)象,。此研究中,，Andrea  Richardson  博士等人則針對偶發(fā)性  BLC  異常表達(dá)與  Xi  染色體管理的關(guān)聯(lián)進(jìn)行分析。

        結(jié)果發(fā)現(xiàn),，許多偶發(fā)性  BLC  都有  Xi  缺失的情形,。這些腫瘤也有X  染色體上特定基因表達(dá)增加的情況。所分析的  BLC  BRCA1  基因正常,，表明其它與細(xì)胞路徑有關(guān)的基因出現(xiàn)異常,。研究人員表示,，這項分析發(fā)現(xiàn)偶發(fā)性和與  BRCA1  

        有關(guān)的乳癌新致病機制。而更深入地了解兩個活化的  X  染色體與癌癥發(fā)展的關(guān)聯(lián)性,，將有助于乳腺癌新療法的研發(fā),。

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.

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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/