BRCA1 mediates the repression of select X chromosome genes

Abstract

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Objectives: Recently it has been proposed that BRCA1 may be involved in the regulation of gene expression from the X chromosome. This hypothesis is based on newly discovered interactions between BRCA1 and XIST, a non-translated RNA that normally coats the inactive X chromosome. In this study the influence of BRCA1 on the expression of X chromosome genes was investigated in ovarian cancer samples. Methods: Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 “BRCA1-like” and 14 “BRCA2-like” sporadic tumors (as defined by previously reported expression profiling). Significance was determined using parametric statistics with P<0.005 as a cutoff. Virally-mediated BRCA1 re-expression in HCC1937 BRCA1-deficient breast cancer cells was also performed to complement our in vivo studies. Results: Forty of 178 total X-chromosome transcripts were differentially expressed between the BRCA1-associated tumors and sporadic cancers with a BRCA2-like molecular profile. Thirty of these 40 genes showed higher mean expression in the BRCA1-associated samples including all 11 transcripts that mapped to Xp11. In contrast, four of 178 total X chromosome transcripts showed significant differential expression between BRCA1-associated and sporadic tumors with a BRCA1-like molecular profile. All four mapped to Xp11 and showed higher mean expression in BRCA1-associated tumors. Re-expression of BRCA1 in HCC1937 BRCA1-deficient breast cancer cell resulted in the repression of 21 transcripts. Eleven of the 21 (54.5%) transcripts mapped to Xp11. Conclusions: These findings demonstrate that wild-type BRCA1 mediates the repression of several X chromosome genes, many of which map to the Xp11 locus. In addition, tumors from patients with BRCA1 germ-line mutations show significantly higher mean expression levels of genes mapped to Xp11. Future investigations are needed to address the mechanism for this repression.