Decreased Phosphorylation of RSK May Predict Response for Neoadjuvant Chemotherapy.

Abstract

Abstract Neo-adjuvant chemotherapy is an essential part of the management of locally advanced breast cancer. The resistance in breast cancer towards chemotherapeutic agents makes chemotherapy an incommodious problem. Current clinical factors cannot predict therapy response sufficiently in the treated patients. Doxorubicin is an effective breast cancer drug but is hampered by a severe, dose-dependent toxicity. The resistance mechanisms responsible for doxorubicin-resistance of breast cancer have been the subject of numerous investigations. Identification of proteins that are associated with doxorubicin resistance is a first step toward better response prediction and tailored treatment of patients.In this study, we compared the expression of core proteins and their phosphorylated forms of several canonical pathways (MAPK signaling, Apoptosis, PI3K/Akt Signaling, Cell Cycle/Checkpoint and TGF-β/Smad signaling) in breast cancer tissues which were divided into two classes based on the type of response to doxorubicin therapy by immunoblotting. As a result, we found that the phosphorylated form of ribosomal protein S6 kinase (RSK) was low in doxorubicin-resistant breast cancer tissues compared with doxorubicin-sensitive breast cancer tissues.We also investigated RSK's phosphorylation rate and doxorubicin sensitivity of various breast cancer cell lines including MCF-7, MCF-7s (sphere form), MDA-MB-231, MDA-MB-231s, MDA-MB-436, MDA-MB-453, MDA-MB-468, ZR75-1, BT474, Hs578T, T47D and MCF-10A to determine the phosphorylation rate of RSK in relation to the drug sensitivity of the breast cancer cell lines. Expectedly, the phosphorylation of RSK was low in doxorubicin resistant breast cancer cell line such as MDA-MB-453, ZR75-1 and Hs578T. Additionally, MCF-7s and MDA-MB-231s showed decreased phosphorylation rates compared with MCF-7 and MDA-MB-231.In conclusion, decreased phosphorylation of RSK may predict response and further clinical studies should evaluate for molecular function of phosphorylated RSK during doxorubicin therapy. Furthermore, immunohistochemistry for the detection of RSK's phosphorylation rate in breast cancer tissues is being developed for the analysis of increased and independent group of patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2146.