Abstract B34: Increase in EGFR level through SLUG-induced repression of dynactin 5 in triple-negative breast cancer cells

Aggressive breast cancers of the triple negative type (TNBCs) are often characterized with higher levels of receptor tyrosine kinases (RTKs; e.g. EGFR) and G-protein coupled receptors (GPCRs; e.g. PAR1). These receptors are activated by their agonists, induce signal transduction and then are attenuated by signal uncoupling and retrograde recycling endosome transport. We report here that the levels of several of these receptor proteins are elevated and hyperactivated on the surface of aggressive breast cancer cells that have high levels of the transcriptional repressor protein SLUG. Chip-on-chip analysis to identify genes that are repressed by SLUG in the breast cancer cells revealed one of the proteins that are critical for the retrograde recycling transport of the RTKs and GPCRs, namely dynactin 5 (DCTN5). DCTN5 (aka p25) is a member of the dynactin complex. DCTN5 is a subunit of the pointed-end subcomplex of dynactin that is thought to interact with membranous cargo. Interestingly, DCTN5 is expressed from the reverse activity of the bidirectional promoter of human PALB2 (partner and localizer of BRCA2) gene whose product regulates the functions of the tumor suppressor protein BRCA2. We found that SLUG inhibits both PALB2 and DCTN5 gene expression through chromatin remodeling in human breast cancer cells. We hypothesize that the malignant breast cancer cells acquire highly aggressive and metastatic characteristics in part due to the higher levels and hyperactivation of EGFR on their surface. The hyperactivity of EGFR occurs through the SLUG-mediated repression of DCTN5 which mediates the internalization and thus, degradation of activated receptors. We evaluated the role of DCTN5 in the determination of aggressiveness in TNBC cells. We postulate that maintenance of normal levels DCTN5 in the TNBC cells through the inhibition of the functions of SLUG will control the invasive growth of the breast tumors. Supported in parts by the DOD-CDMRP grants BC050641, BC086542 and BC103645.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B34.