The regulation of BMI1 in breast cancer cell lines
Open AccessTo study the molecular mechanisms that regulate the expression of BMI1 in breast cancer cells, we carried out a study using normal immortal human mammary epithelial cell (HMEC) line MCF10A and Inflammatory Breast Cancer (IBC) cell lines SUM149PT and SUM159PT. Previous studies have shown SUM149PT to contain an FBW7 (F-box and WD40 repeat domain-containing 7 protein) mutation at the hCdc4 locus resulting in deletion of the last four of seven WD40 repeats of the protein, which are important for its function in ubiquitin-proteosome mediated degradation of proteins. Based on the presence of consensus binding sites for FBW7 in BMI1 protein, we hypothesized that FBW7 may regulate BMI1 expression. FBW7 is a tumor suppressor that is frequently inactivated or deleted in a wide range of human tumor types. It functions as a substrate recognition component of the SFC-type ubiquitin ligase, and regulates the rate of protein turnover for specific oncoproteins by targeting them for proteosomal degradation. Mutations that compromise the function of FBW7 lead to chromosomal instability, aberrant protein degradation and tumorigenesis. The exact mechanism regulating the overexpression of BMI1 is not very well understood. In this study, we show the upregulation of BMI1 in FBW7 mutant cell lines at both transcriptional and posttranslational levels. We also show that BMI1 remains stable in FBW7 mutant cell lines after treatment with DNA damage-inducing drugs, but decreases in FBW7 wild type cell lines. In summary, our findings suggest that FBW7 regulates turnover of BMI1 in both normal HMEC as well as in IBC cell lines, and that loss of function of FBW7 causes deregulation of BMI1, resulting in its overexpression in breast cancer cell lines.
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