Elucidation of the Molecular Mechanisms for Aberrant Expression of Breast Cancer Specific Gene 1 in Invasive and Metastatic Breast Carcinomas

摘要

Breast cancer specific gene 1 (BCSG1) is not expressed in normal breast tissue but is highly expressed in the vast majority of invasive and metastatic breast carcinomas. When over expressed, BCSG1 significantly stimulates the proliferation and invasion of breast cancer cells. However, the mechanisms that turn on the BCSG1 transcription in breast cancer cells were largely unknown. In the first year of funding, we extensively examined the methylation status of a CpG island located in the exon 1 of BCSGl gene in a panel of breast tumor-derived cell lines to determine whether DNA methylation plays a crucial role in BCSGl expression. In-vivo bisulfite DNA sequencing of genomic DNA isolated from breast cancer cell lines showed that the 15 CpG sites within the CpG island were completely unmethylated in all BCSG1- positive cell lines (515), but were densely and heterogeneously methylated in the majority of BCSGl-negative cell lines (314). A correlation between hypomethylation of the exon 1 and expression of BCSGl mRNA was also verified in primary breast tumor tissues. In addition to the methylation control we also demonstrate that the binding of c-jun to two Ap1 sites located in the first intron is critical for BCSGl transcription in cells that have unmethylated BCSGl gene. Inhibition of Ap1 transactivation by using its dominant negative mutant severely reduced BCSGl expression in breast cancer cells.