The Prognostic Role of IRS2 in Breast Cancer: Interactions with Glucose Metabolism and Menopausal Status

The Insulin Receptor Substrate 2 (IRS2) gene encodes an adapter protein that transmits insulin signals to regulate various cell functions, including metabolism, growth, and survival. Dysregulation of IRS2 activity is often associated with obesity and type 2 diabetes. Both conditions are strongly associated with a higher breast cancer risk. IRS2 is predominantly regulated in various tissues at the level of expression; however, the association between tumor IRS2 expression and certain clinical factors, such as diabetes status and menopausal status, and their effects on breast cancer prognosis are not fully understood. To address this gap, we utilized five datasets of bulk RNA-seq data of patients with breast cancer from the Xena Functional Genomics Explorer, and primarily analyzed the TCGA Breast Cancer Cohort, which includes data from 1097 patients with primary breast tumors. We complemented these transcriptomic analyses by using 3′-Deoxy-3′-18F-Fluorothymidine positron emission tomography-computed tomography (¹⁸F-FLT PET-CT) scans from 23 patients that were publicly available from the Cancer Imaging Archive (TCIA) to correlate this marker of tumor cell proliferation with body mass index (BMI) and glucose levels (as a proxy for diabetes), and further divided data by menopausal status. Through deidentified, publicly available data, the study explores the effects of IRS2 expression on breast cancer in different cohorts, as well as the role of menopausal status in this dynamic and the context of obesity and diabetes.