Abstract
Trastuzumab, the first antibody widely used in anti-HER2 targeted therapy, dramatically improved the overall outcome of HER2 positive breast cancer patients. However, trastuzumab resistance emerged as a major problem in its clinical application. In order to explore mechanisms underlying trastuzumab resistance, we performed RNA-Seq to analyze the gene expression variation in trastuzumab resistant breast cancer cell line. The sequencing result was then combined with the relevant data in TCGA database to conduct a co-expression analysis. We found a series of differentially expressed genes with potential contributions to trastuzumab resistance. Among them, KLK10 was verified to be a potential therapeutic target for reversing trastuzumab resistance. In summary, this study provides a new clue to screen molecular targets and predictive biomarkers for trastuzumab resistance.
Highlights
Breast cancer accounts for the highest morbidity and mortality among all cancers in female globally [1]
High KLK10 expression was associated with poor prognosis of breast cancer, indicating that KLK10 is a potential target and prognosis predictor for trastuzumab resistance
There are 246 genes detected to be statistically significant differentially expressed between BT474 and BT474 HR cells, some may have no relevance to trastuzumab resistance per se
Summary
Breast cancer accounts for the highest morbidity and mortality among all cancers in female globally [1]. 30% breast cancer patients have HER2 gene amplification [2]. Trastuzumab, the first antibody widely used in anti-HER2 targeted therapy, dramatically improved the overall survival of HER2 positive breast cancer patients. It has been approved to treat HER2 positive gastric cancer [3]. Novel targets are expected to reverse trastuzumab resistance. No effective targets or biomarkers have been approved for trastuzumab resistance. Most of such efforts to identify biomarkers or targets for trastuzumab resistance were based on the molecular mechanism of trastuzumab [4, 5]. More practical alternative approaches would be necessary to identify biomarkers to predict and targets to reverse trastuzumab resistance
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