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Inactivation of Human SRBC, Located within the 11p15.5-p15.4 Tumor Suppressor Region, in Breast and Lung Cancers¹

Hamon Center for Therapeutic Oncology Research [X. L. X., M. P., Y. T., A. M., G. T., A. F. G., J. D. M.], and Department of Biochemistry [L. C. W.], University of Texas Southwestern Medical Center, Dallas, Texas 75390; Institute of Cancer Genetics, Columbia University College of Physicians and Surgeons New York, New York 10032 [R. B.]; Division of Human Genetics, Department of Genetics, Pediatrics and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 [F. D., A. M. B.]; Department of Pathology and Laboratory Medicine and The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 [A. D., B. E. W.]

A cDNA clone encoding human SRBC [serum deprivation response factor (sdr)-related gene product that binds to c-kinase] was isolated in a yeast two-hybrid 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 marker D11S1323, at which frequent loss of heterozygosity (LOH) has been observed in sporadic breast, lung, ovarian, and other types of adult cancers as well as childhood tumors. hSRBC-coding region mutations including frame shift and truncation mutations were detected in a few ovarian and lung cancer cell lines. More significantly, the expression of hSRBC protein was down-regulated in a large fraction [30 (70%) of 43] of breast, lung, and ovarian cancer cell lines, whereas strong expression of hSRBC protein was detected in normal mammary and lung epithelial cells. The down-regulation of hSRBC expression in cancer cells was associated with hypermethylation of CpG dinucleotides 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. Treatment of breast cancer MCF7 cells with 5'azacytidine and Trichostatin A resulted in expression of hSRBC, confirming DNA methylation as the mode of inactivation. Our results suggest that epigenetic or mutational inactivation of hSRBC may contribute to the pathogenesis of several types of human cancers, marking hSRBC as a candidate tumor suppressor gene.

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