Abstract A001: Transcriptomic and microRNA profiling revealed novel therapeutic targets for breast cancer subtypes

Numerous studies suggested breast cancer (BC) from the Middle East and North Africa (MENA) to be presented at younger age with advanced tumor grade, suggesting underlying biological differences. Given the limited transcriptomic profiling data on BC from the MENA region, we performed mRNA and microRNA (miRNA) transcriptomic profiling on a local cohort of BC (n=96) from Qatar. Our data revealed the differentially expressed genes and miRNAs in relation to BC molecular subtypes (HR+, HER2+, HER2+HR+, and TNBC), tumor grade (high vs low), patients’ age (young (≤ 40) vs old (> 40)), and ethnicity (MENA vs non-MENA). Our data revealed close similarity between TNBC and HER2+, while the transcriptome of HER2+HR+ tumor was similar to that from HR+ tumors. Integrated network analysis identified complex miRNA-mRNA regulatory networks in each BC molecular subtype, in high vs low grade tumors, in tumors from young vs old, and in tumors from MENA vs non-MENA, thus implicating miRNA-mediated gene regulation as an key mechanism in shaping the transcriptome of BC. Integration of our transcriptomic data with CRISPR-Cas9 functional screen data and the Drug-Gene Interaction Database identified numerous dependencies and therapeutic vulnerabilities for each BC molecular subtype. Among those, CDC123 was functionally validated as potential therapeutic target for TNBC. Survival analyses identified mRNA and miRNA-based signatures predicative of relapse free survival (RFS), which were validated in larger BC cohorts. Our data provides comprehensive transcriptomic profiling and unraveled the miRNA-mRNA regulatory networks in BC patients from the region and identified numerous actionable gene targets, employing integrated approach. Findings from the current study have potential implications to improve the current standard-of-care for BC from the MENA as well as patients from other ethnicities.