BRCA1 Partially Reverses the Transforming Activity of the ras Oncogene

Abstract

The BRCA1 gene is associated with hereditary breast and ovarian cancers. BRCA1 fits the model of a classic tumor suppressor gene, a hypothesis supported by recent work demonstrating that expression of BRCAi inhibits growth of breast and ovarian cancer cell lines. The present study was designed to test the potential of BRCAi to reverse the transforming activity of the ras oncogene. The v-Ha ras oncogene was cloned downstream of the retrovirus LTR and stably expressed in Rat-1 cells (Rat-1/ras). Rat-1/ras (R/R) cells were fully transformed as indicated by change in morphology, colony formation in soft-agarose and tumor induction in nude mice. BRCAi was stably expressed in R/R cells under the CMV promoter (R/R-BRCA1). The expression of ras and BRCAi was confirmed by Western blot using monoclonal antibodies (mAbs) specific to ras and BRCA1, respectively. R/R-BRCA1 cells grew slower than the negative control, which was R/R cells transfected with vector alone (R/R-pCEP4). R/R-BRCA1 cells generated ~5 to 10 times less colonies in a soft-agarose assay compared to the negative control. When injected into nude mice, R/RBRCA1 cells exhibited a delayed onset of tumorigenesis and generated smaller tumors compared to R/R or R/RpCEP4 cells. These data strongly suggest that BRCA1 partially reverses the transforming activity of the v-Ha ras oncogene indicating that BRCA1 can bypass the effects of the v-Ha ras oncogene on cell growth. BRCA1, therefore, may be used in therapy of tumors arising due to activation of v-Ha ras oncogene.

Keywords

• BRCA1
• breast cancer
• tumor suppressor
• ras
• oncogene