Abstract B35: SLUG-induced plakoglobin gene repression in triplenegative breast cancer cells

• Published in: Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 2011-09, Vol.20 (10_Supplement), p.B35-B35
• Main Authors: Bailey, Charvann K., Mittal, Mukul K., Misra, Smita, Chaudhuri, Gautam
• Format: Article
• Language: English
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.DISP-11-B35

Breast cancer with the triple-negative phenotype (TNBC) are ER-negative, PR-negative and ERBB2 (HER2)-negative and represent one of the most aggressive and difficult to treat subtypes of human breast cancer. TNBC is highly over-represented in African American breast cancer patients and determining the genetic and molecular basis for this incidence and the biological basis for the aggressiveness of TNBCs are largely unknown and of high priority. The transcription factor SLUG, which controls epithelial to mesenchymal transition, stem cell phenotypes and therapeutic responsiveness, is highly expressed in the basal-type TNBC cells, making it a candidate master regulator of the TNBC phenotype. Plakoglobin, also known as γ-catenin or JUP, is a member of the armadillo motifcontaining proteins. This protein is a critical component of the desmosomal structure conferring structural integrity and resistance from mechanical stress to epithelial cells in tissues. We report here that SLUG inhibits the expression of several desmosomal proteins including the plakoglobin gene directly and thus, among other downstream effects, help disseminating the TNBC cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high TNBC cells elevated the levels of plakoglobin. Inhibition of SLUG activity with a molecular decoy in the TNBC cells abrogated the inhibitory effect of SLUG on plakoglobin gene expression. Although overexpression of SLUG in the SLUG-deficient cells elevated the invasiveness and motility of these cells, knockdown of plakoglobin only affected the growth and migration rates of these cells. This study thus implicates high levels of SLUG and low levels of plakoglobin as determinants in the progression of highly disseminating breast cancer of the TNBC type. Supported by the DOD-CDMRP BCRP Grants W81XWH-06-1-0466, W81XWH-08-1-0446, BC086542, and the Susan G. Komen Breast Cancer Foundation grant# BCTR0707627 to GC. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B35.