Isolation of a Breast Cancer Tumor Suppressor Gene from Chromosome 3P

摘要

Loss of tumor suppressor genes (TSGs) represent critical molecular events in the development and progression of breast cancer. Based on loss of heterozygosity (LOH) studies as well as direct cytogenetic studies of breast tumors, one or more TSGs likely resides on the short arm of chromosome 3 (3p) and appears to be involved in nearly 50% of breast cancers. Four distinct regions within 3p P12, P14, P21 (PROXIMAL) AND P21 (DISTAL) undergo recurrent deletions in human carcinomas and are the most likely sites for a breast cancer TSG. In this Final Progress Report, we describe the full spectrum of investigations we have conducted to identify tumor suppressor genes and to begin to understand their functions. Early in our studies, we demonstrated recurrent homozygous deletion or rearrangement in breast cancer cell lines involving 3p 14. The critical region was cloned and sequenced which led to the identification of several putative exons. We determined that 3p14 is subject to a high degree of genomic instability which is ongoing in some cases. We evaluated other 3p regions for involvement in breast cancer, as originally proposed, including the 3p21.31 and 3p21.33 homozgyous deletion regions as well as the interval between. Our studies led to the discovery of a novel patched-related gene, TRC8, which resides in a chromosomal region with frequent amplification in breast tumors. Current evidence suggests this gene will be important in early embryogenesis and may identify a new pathway for cancer development.