Elucidating the Role of iRhoms in Breast Cancer as Potential Therapeutic Targets Using Meta Co-Expression Analysis

Abstract

Breast cancer is the second most common cancer worldwide as well as in Pakistan. iRhoms are inactive rhomboid proteases play a diverse regulatory role in mammals. iRhoms are remarkable targets to treat TACE or EFGR-dependent pathological diseases and cancers. This study was designed to provide a clear understanding of the expression and regulation of both iRhom1 and iRhom2 in breast cancer. Meta differential expression analysis revealed that iRhom1 was significantly down regulated, whereas iRhom2 showed heterogenous behaviour in breast cancer patients. RT-qPCR analysis was performed to check the expression of iRhoms in Pakistani population using blood sample of patients. Furthermore, a systematic methodology was employed for meta differential expression analysis and meta correlation analysis to find interacting proteins with iRhom1 and iRhom2. Meta transcriptome analysis of RNA-seq datasets showed that iRhoms are not significantly connected to ADAM17 in breast cancer thus do not support the hypothesis that “iRhoms are upstream regulators of ADAM17”. iRhom1 is involved in metastasis and angiogenesis incorporation with AXIN which connects iRhom1 with MYC (a gene involved in breast cancer). Study showed significant role of iRhom1 in breast cancer and upregulation of iRhom1 can suppress breast cancer. The possible pathway of iRhom1 in the MAPK, TNF-α and breast cancer pathway in association with AXIN1 and DOCK6, and low expression of iRhom1 can cause neoplasm formation, angiogenesis that ultimately leads to breast cancer. This study enhanced the current understanding about the functional characterization of iRhom1 in breast cancer that will further contribute to its assessment as a potential therapeutic target. However, the specific mechanism needs to be confirmed by subsequent experiments.