Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers

A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-r elated gene product that binds to c-kinase] was isolated in a yeast two-hyb rid screening, with amino acids 1-304 of BRCA1 as the probe. The human SRBC gene (hSRBC) was mapped to chromosome region 11p15.5-p15.4, close to marke r D11S1323, at which frequent loss of heterozygosity (LOH) has been observe d in sporadic breast, lung, ovarian, and other types of adult cancers as we ll as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer ce ll lines. More significantly, the expression of hSRBC protein was down-regu lated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian can cer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expr ession in cancer cells was associated with hypermethylation of CpG dinucleo tides in its promoter region, and 3 (60%) of 5 primary breast tumors and 11 (79%) of 14 primary lung tumors were also found to be hypermethylated. Tre atment of breast cancer MCF7 cells with 5' azacytidine and Trichostatin A r esulted in expression of hSRBC, confirming DNA methylation as the mode of i nactivation. Oar results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human canc ers, marking hSRBC as a candidate tumor suppressor gene.