Abstract
Breast cancer is one of the most common malignant cancers affecting females. Estrogen receptor (ER)-positive breast cancer is responsive to endocrine therapy. Although current therapies offer favorable prospects for improving survival, the development of resistance remains a severe problem. In this study, we explored the resistance mechanisms of ER-positive breast cancer to neoadjuvant endocrine therapy. Microarray data of GSE87411 contained 109 pairs of samples from Z1031 trial, including untreated samples and post-treated samples with neoadjuvant aromatase inhibitor (AI) therapy. The differentially expressed genes (DEGs) were obtained from two different comparisons: untreated samples versus post-treated samples with AIs, and post-treated samples sensitive versus resistant to AIs. Multiple bioinformatic methods were applied to evaluate biological function, protein-protein network and potential binding between target protein and aromatase inhibitor. Then, regulation of gene expression, DNA methylation and clinicopathological factors of breast cancer were further analyzed with TCGA data. From GSE87411 dataset, 30 overlapped DEGs were identified. Cell division was found to be the main function of overlapped DEGs by functional enrichment and gene ontology (GO) analysis. RAD51 recombinase (RAD51), a key protein of homologous recombination, was detected to interact with BReast CAncer genes 2 (BRCA2). Moreover, according to the docking simulation, RAD51 might potentially bind to AIs. Overexpressed RAD51 was associated with hypermethylation of BRCA2, resistance to AIs and poor overall survival of patients with ER-positive breast cancer. Furthermore, RAD51 was found to be a better indicator than MKI67 for predicting resistance in neoadjuvant setting. The results indicated that methylation of BRCA2 led to incomplete suppression on RAD51, which caused an increased expression of RAD51, subsequently AI-resistance and poor prognosis in ER-positive breast cancer. RAD51 could be a new candidate used as a predicative marker and therapeutic target in neoadjuvant endocrine treatment.
Highlights
The GSE87411 microarray data was divided by the GEO2R online software into two pairs of groups, which were defined as T-group and R-group
82 differentially expressed genes (DEGs) were discovered to be dysregulated in T-group
The expression of overlapped DEGs was significantly downregulated after neoadjuvant aromatase inhibitor (AI)-treatment, and upregulated in AI-resistant samples compared with AI-sensitive samples (Fig. 1C)
Summary
Some patients with ER-positive cancer who initially respond would later become refractory to endocrine therapy (acquired resistance)[9]. Several strategies including tyrosine kinase inhibitor, multi-kinase inhibitor, or manipulation of growth factor signaling come out. They may provide hope to patients who are suffering from the resistance to endocrine therapy[9]. The trial was designed to determine which aromatase inhibitor (Anastrozole, Letrozole or Exemestane) or subset of agents should be recommended for future evaluation against chemotherapy in neoadjuvant setting based on differences in clinical response rates after 16 weeks of treatment[8,10,11]. We explored the molecular mechanisms of resistance in order to acquire candidate markers to personalize neoadjuvant strategy for ER-positive breast cancer
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