Gene Identified as DNA Protector, Tumor Foe

Anderson Cancer Center (Houston, USA) reported their findings in the August 2006 advance online issue of the journal Cancer Cell. The study also reported that the gene--called BRIT1--is underexpressed in human ovarian, breast, and prostate cancer cell lines.

Defects in BRIT1 seem to be a crucial pathologic alteration in cancer initiation and progression, the researchers observed, and further understanding of its function may contribute to new therapeutic approaches to cancer. "Disruption of BRIT1 function abolishes DNA damage responses and leads to genomic instability,” said senior author Shiaw-Yih Lin, Ph.D., assistant professor in the department of molecular therapeutics at M.D. Anderson. Genomic instability promotes the initiation, growth, and metastasis of cancer.

A signaling network of molecular checkpoint pathways protects the human genome by detecting DNA damage, initiating repair, and halting division of the damaged cell so that it does not replicate. In a series of laboratory studies, Dr. Lin and colleagues demonstrated that BRIT1 activates two of these checkpoint pathways. The ATM pathway becomes activated in response to damage caused by ionizing radiation. The ATR pathway responds to DNA damage caused by ultraviolet radiation.

By using small interfering RNA (siRNA) to silence the BRIT1 gene, the scientists blocked both checkpoint pathways in cells exposed to either type of radiation. Researchers then utilized siRNA to silence the gene in healthy human mammary epithelial cells (HMECs). The result was inactivation of the gene caused chromosomal aberrations in 21.2-25.6% of cells. Control group HMEC had no cells with chromosomal abnormalities. In cells with the gene silenced that were then exposed to ionizing radiation, 80% of cells had chromosomal aberrations.

"We also found that BRIT1 expression is aberrant in several forms of human cancer,” Dr. Lin said. The group found decreased expression of the gene in 35 of 87 cases of advanced epithelial ovarian cancer. They also observed a reduced expression in breast and prostate cancer tissue compared with non-cancerous cells. Genetic analysis of breast cancer specimens revealed a truncated, dysfunctional version of the BRIT1 protein in one sample.

Loss of the DNA damage checkpoint function and the ability to proliferate indefinitely are two cellular alterations required for the development of cancer. The researchers have now tied the gene to both factors. They earlier identified BRIT1 as a repressor of hTERT, a protein that when reactivated immortalizes cells, allowing them to multiply indefinitely.



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M.D. Anderson Cancer Center