Multidrug resistance and disease relapse is a challenging clinical problem in the treatment of breast cancer. In this study we investigated the hyaluronan (HA)-induced interaction between CD44 (a primary HA receptor) and protein kinase Cε (PKCε) which regulates a number of human breast tumor cell functions. Our results indicate that HA binding to CD44 promotes PKCε activation which, in turn, increases the phosphorylation of the stem cell marker, Nanog, in the breast tumor cell line, MCF-7. Phosphorylated Nanog is then translocated from the cytosol to the nucleus and becomes associated with RNase III DROSHA and the RNA helicase, p68. This process leads to microRNA-21 (miR-21) production, and a tumor suppressor protein [e.g., the Program Cell Death 4 (PDCD4)] reduction. All of these events contribute to upregulation of inhibitors of apoptosis proteins (IAPs, e.g., XIAP and survivin) and the multidrug resistant protein (MDR1)/P-glycoprotein (P-gp) resulting in anti-apoptosis and chemotherapy resistance.

Transfection of MCF-7 cells with PKCε or Nanog-specific small interfering RNAs (siRNAs) effectively blocks HA-mediated PKCε/Nanog signaling events, abrogates miR-21 production and increases PDCD4 expression/eIF4A binding. Subsequently, this PKCε/Nanog signaling inhibition causes IAP/MDR1 (P-gp) downregulation, apoptosis and chemosensitivity. To further evaluate the role of miR-21 in oncogenesis and chemoresistance, MCF-7 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and inhibit its target functions. Our results indicate that anti-miR-21 inhibitor not only enhances PDCD4 expression/eIF4A binding, but also blocks HA/CD44-mediated tumor cell behaviors [e.g., IAP/MDR1 (P-gp) upregulation, anti-apoptosis and chemotherapy resistance] in MCF-7 cells. Taken together, these findings suggest that the HA-induced CD44 interaction with PKCε plays a pivotal role in Nanog signaling and miR-21 production leading to the tumor suppressor protein (PDCD4) downregulation, anti-apoptosis/survival and chemoresistance. Thus, this newly-discovered HA/CD44 signaling pathway should provide important drug targets for sensitizing tumor cell apoptosis and overcoming chemotherapy resistance in breast cancer cells.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2039.