1895

Gene amplification of the chromosome 8p11-12 region has been reported in 10-15% of human breast cancers, but the specific genes within this amplicon that are responsible for mediating the cancerous phenotype have yet to be characterized. Studies in our laboratory have identified a number of target genes in this region that are amplified, highly over-expressed, and may contribute to cancer progression, one of which is Sm-like protein-1 (Lsm1) or cancer-associated Sm-like protein (CaSm). Lsm1 is a factor shown to be important for mRNA decay through the formation of a 7-member structure with other Lsm family members. It was originally identified as an up-regulated gene in human pancreatic cancer and further shown to be responsible for maintaining the transformed phenotype of these cancers. Previous data from our laboratory have shown an approximate 4-fold amplification in Lsm1 DNA and a 4-fold over-expression of Lsm1 mRNA in the SUM52 and SUM44 breast cancer cell lines, as compared to human mammary epithelial (HME) cells. Both of these cell lines have an amplicon in the chromosome 8p11 region, suggesting that Lsm1 may be one of the important oncogenes influencing the pathology of breast cancers containing this amplicon. To investigate the oncogenic potential of Lsm1, we first established that Lsm1 protein was over-expressed approximately 5-fold in breast cancer cell lines compared to normal HME cells, which follows the pattern observed for Lsm1 mRNA expression. Subsequently, two HME cell types, MCF10A and MCF10A transduced with the HPV-16 E6 and E7 oncoproteins, were infected with an Lsm1 lentiviral expression vector in order to determine the transforming ability of this factor. Both of these recipient cell lines have been used routinely and effectively in our laboratory to identify and validate oncogenes based on their ability to alter HME and induce transformed phenotypes. Increased Lsm1 mRNA expression and protein production in cells infected with the Lsm1 vector conferred growth factor-independent proliferation not seen in cells infected with a control vector. Specifically, Lsm1-infected MCF10A cells grew in the absence of insulin and Lsm1-infected MCF10A-E6/E7 grew without epidermal growth factor, suggesting that Lsm1 may be one of the important oncogenes responsible for driving the transformed phenotype of SUM52 and SUM44 breast cancer cell lines. Characterizing novel oncogenes present within the chromosome 8 amplicon could contribute to the development of new therapeutic strategies with the ability to affect a substantial proportion of human breast cancers.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]