Computational Identification of Sex-Biased Biomarker MicroRNAs and Genes Associated with Immune Infiltration in Breast Cancer

MicroRNAs (miRNAs) perform their functions through targeting messenger RNAs (mRNAs). X chromosome-located (X-linked) miRNAs have a broad role in cell lineage determination, immune regulation, and oncogenesis. The regulating roles of miRNAs in cancer and immunity are often altered when aberrant expression happens. Sex-biased genes could contribute to cancer sex bias in the context of their expression change due to targeting miRNAs. How biological roles and associations with immune cell abundance levels for sex-biased gene-miRNA pairs in gender-related cancer (e.g., breast cancer) change due to the alteration of their expression pattern to identify candidate therapeutic markers has not been investigated thoroughly. Upon analyzing anti-correlated genes and miRNAs within significant clusters of 12 The Cancer Genome Atlas (TCGA) cancer types and the list of sex-biased genes and miRNAs reported from previous studies, 125 sex-biased genes (11 male-biased and 114 female-biased) were identified in breast cancer (BC). Seventy-three sex-biased miRNAs (40 male-biased and 33 female-biased) were identified across 5 out of 12 cancers (head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and lung adenocarcinoma (LUAD)). Correlation between the BC sex-biased genes and tumor infiltrating immune cell types was further evaluated. We found eight genes having high correlation with immune infiltration. Fifteen candidate female-biased BC genes targeted by 3 X-linked miRNAs (has-mir-18hashsa-mir-221, and hsa-mir-224) were pinpointed in this study. Our computational result indicates that many identified female-biased genes which have positive associations with immune cell abundance levels could serve as alternative therapeutic markers. Our analysis suggests that female-biased expression of BC candidate genes is likely influenced by their targeting miRNA(s).