Abstract 1460: Co-expression network analysis reveals male breast cancer specific transcriptional module

Abstract

Abstract Introduction: According to the American Cancer Society, An estimated 2,710 men are diagnosed with breast cancer annually of which about 530 die due to the disease annually in the United States. Most male breast tumors are estrogen receptor positive. Risk factors include age, radiation exposure, BRCA1/2 gene mutations, Klinefelter syndrome, testicular disorders, diabetes, gynecomastia (enlarged breast) etc. Due to low testing and incidence rate and lack of bioinformatics approaches focused on identification of drivers of rare cancer, little is known about this disease in men than in women. Because of this knowledge-gap there is no therapy that is specifically tailored for male breast cancer, leading to nineteen percent higher mortality in male than female with breast cancer. Method: In the past, gene expression analysis has revealed differential pathways in male than in female breast cancer, but these studies compared male and female tumors without considering innate (sex-specific) differences in the mammary tissues between the two sexes. To overcome these challenges, we have utilized publicly available tumor (E-TABM-810, TCGA-Breast) and normal (GTEX - mammary) datasets to identify pathways and gene co-expression networks enriched in specific transcription factor (TF) targets that are specific to male breast tumors . Findings from this analysis is further validated in male breast tumor patient derived xenograft (PDX) model. Result: Using differential pathway analysis corrected by sex, Type I diabetes mellitus is the only Hallmark pathway signature that is significantly downregulated in male tumors compared to both female tumors and normal mammary tissue. No pathway is distinctively up-regulated in male tumors. Co-expression network analysis of gene expression datasets identified unique TF-driven networks that are specific to male breast tumors. This analysis identified a network of ELK1 and DMRT1 TF targets that are unregulated and downregulated in male breast tumors respectively. This was further validated in PDX dataset. Conclusion: Based on our results, we hypothesize that loss of DMRT1 TF activity is potentially associated with occurrence of male breast tumors. The role of DMRT1 in sex differentiation and gonadal differentiation has been explored, but its role in male breast tumor formation is not as well characterized. Thus, our analysis provides novel insight in transcription factors associated with incidence of this rare form of cancer in men. Citation Format: Xuxu Gou, Junkai Wang, Jonathan T. Lei, Eric J. Jaehnig, Meenakshi Anurag. Co-expression network analysis reveals male breast cancer specific transcriptional module [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1460.