The Y-box binding protein-1 (YB-1)/epidermal growth factor receptor (EGFR) pathway are frequently expressed in basal-like breast cancer and provides opportunities for targeted therapies Free

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Basal-like breast cancers (BLBC) are very aggressive and present serious clinical challenges as there are currently no targeted therapies for this subtype of cancer. They are ER, PR and Her-2 negative, and therefore unresponsive to hormone therapy and Herceptin, the frontline targeted therapies agents for breast cancer. Treatment with conventional chemotherapy is largely unsuccessful resulting in poor survival rates beyond one year. The molecular events involved in the development of basal-like breast cancer are unclear. We have previously demonstrated elevated levels of the transcription factor Y-box binding protein-1 (YB-1) in breast cancer and now using a tumor tissue microarray of 438 cases we determined that YB-1 is expressed in 73% (27/37 cases, p<0.001) of BLBC and furthermore, this expression correlated with the new BLBC markers epidermal growth factor receptor (EGFR) and ck5/6 (75%, 21/28 cases, p=0.001). Notably, there was no change in gene copy number for EGFR or YB-1, as assessed by comparative genomic hybridization (CGH), indicating that over-expression was likely due to transcriptional activation. This supports our recent study showing that YB-1 binds to -1kB of the EGFR promoter in other breast cancer subtypes. To further this work, we now demonstrate that YB-1 transactivates the EGFR promoter, through the measurement of luciferase activity. This transcriptional activity is dependent upon phosphorylation at S102 where wild-type YB-1 induced activity 1.5 fold, P=0.04 whereas the mutant YB-1:A102 did not. In SUM149 BLBC cells binding was fine mapped to -940 to -968 first by chromatin immunoprecipitation and more definitively by gel shift. Interestingly, we find that the growth of BLBC cells can be suppressed by up to 80% with the EGFR inhibitor gefitinib, which was independent of activating mutations in the receptor. Moreover, low doses of drug (2.5 micromolar) in combination with YB-1 siRNA suppressed tumor cell growth by ~70%. In conclusion YB-1 is expressed in the majority of BLBC and it provides new opportunities for targeted therapies.