%0 Journal Article
%T Combined Phosphoproteomics and Bioinformatics Strategy in Deciphering Drug Resistant Related Pathways in Triple Negative Breast Cancer
%A Xinyu Deng
%A Morris Kohanfars
%A Huan Ming Hsu
%A Puneet Souda
%A Joe Capri
%A Julian P. Whitelegge
%A Helena R. Chang
%J International Journal of Proteomics
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/390781
%X Because of the absence of a clear therapeutic target for triple negative breast cancer (TNBC), conventional chemotherapy is the only available systemic treatment option for these patients. Despite chemotherapy treatment, TNBC patients still have worse prognosis when compared with other breast cancer patients. The study is to investigate unique phosphorylated proteins expressed in chemoresistant TNBC cell lines. In the current study, twelve TNBC cell lines were subjected to drug sensitivity assays against chemotherapy drugs docetaxel, doxorubicin, gemcitabine, and cisplatin. Based on their half maximal inhibitory concentrations, four resistant and two sensitive cell lines were selected for further analysis. The phosphopeptides from these cells were enriched with TiO2 beads and fractionated using strong cation exchange. 1,645 phosphoprotein groups and 9,585 unique phosphopeptides were identified by a high throughput LC-MS/MS system LTQ-Orbitrap. The phosphopeptides were further filtered with Ascore system and 1,340 phosphoprotein groups, 2,760 unique phosphopeptides, and 4,549 unique phosphosites were identified. Our study suggested that differentially phosphorylated Cdk5, PML, AP-1, and HSF-1 might work together to promote vimentin induced epithelial to mesenchymal transition (EMT) in the drug resistant cells. EGFR and HGF were also shown to be involved in this process. 1. Introduction Breast cancer is the most common cancer in women [1]. Although the overall incidence of breast cancer is rising worldwide, the mortality rate has been decreasing in the United States [2]. The improved survival rate is likely to be a result of the success in early detection and better treatment in patients with positive estrogen receptors (ER), progesterone receptors (PR), or human epidermal growth factor receptor 2 (Her2/neu) breast cancers [3]. Triple negative breast cancers (TNBC) by default have been grouped together because of the lack of ER, PR, and Her2/neu markers [4, 5]. Compared to the other subtypes of breast cancer, these tumors are frequently more aggressive, manifested by a higher distant relapse rate with more frequent visceral as well as central nervous system metastases and higher mortality rate despite chemotherapy [6¨C8]. The heterogeneous biology and histopathology of TNBC underlie the unpredictable responses to chemotherapy and diverse clinical outcomes seen in these patients. The majority of TNBC with relapse is multidrug resistant and ultimately becomes refractory to all therapies [9, 10]. To improve treatment, it is important to develop novel
%U http://www.hindawi.com/journals/ijpro/2014/390781/