Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients
Drug resistance is a major obstacle to the successful chemotherapy. Several ATP-binding cassette (ABC) transporters including ABCB1, ABCC1 and ABCG2 have been known to be important mediators of chemoresistance. Using oligonucleotide microarrays (HG-U133 Plus 2.0; Affymetrix), we analyzed the ABC transporter gene expression profiles in breast cancer patients who underwent sequential weekly paclitaxel/FEC (5-fluorouracil, epirubicin and cyclophosphamide) neoadjuvant chemotherapy. We compared the ABC transporter expression profile between two classes of pretreatment tumor samples divided by the patients’ pathological response to neoadjuvant chemotherapy (residual disease [RD] versus pathologic complete response [pCR]) ABCB3, ABCC7 and ABCF2 showed significantly high expression in the pCR. Several ABC transporters including ABCC5, ABCA12, ABCA1 ABCC13, ABCB6 and ABCC11 showed significantly increased expression in the RD (p<0.05). We evaluated the feasibility of developing a multigene predictor model of pathologic response to neoadjuvant chemotherapy using gene expression profiles of ABC transporters. The prediction error was evaluated by leave-one-out cross-validation (LOOCV). A multigene predictor model with the ABC transporters differentially expressed between the two classes (p≤0.003) showed an average 92.8% of predictive accuracy (95% CI, 88.0–97.4%) with a 93.2% (95% CI, 85.2–100%) positive predictive value for pCR, a 93.6% (95% CI, 87.8–99.4%) negative predictive value, a sensitivity of 88.1%(95% CI, 76.8–99.4%), and a specificity of 95.9% (91.1% CI, 87.8–100%). Our results suggest that several ABC transporters in human breast cancer cells may affect the clinical response to neoadjuvant chemotherapy, and transcriptional profiling of these genes may be useful to predict the pathologic response to sequential weekly paclitaxel/FEC in breast cancer patients.
KeywordsATP-binding-cassette (ABC) transporters breast cancer class prediction neoadjuvant chemotherapy oligonucleotide microarray
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This work was partially supported by funds for the Third Term Comprehensive 10-Year Strategy for Cancer Control and a Grant-in-Aid for Scientific Research and for Health and Labor Science Research Grants, Research on Advanced Medical Technology, H14-Toxico-007. We are grateful to Tokuzo Arao, Tsutomu Ohta, and Takayuki Kinoshita, for their contribution to the article and assistance in collection of clinical data. Analyses were carried out using BRB ArrayTools developed by Dr. Richard Simon and Amy Peng Lam.
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