INSR–PIK3CA Dysregulation as a Molecular Link Between PCOS-Related Insulin Resistance and Endometrial Cancer

Abstract: 

Polycystic ovary syndrome (PCOS) is a common endocrine disorder strongly associated with insulin resistance and an elevated risk of endometrial cancer. To investigate whether shared molecular disruptions underlie this link, genomic, transcriptomic, and proteomic data from The Cancer Genome Atlas (TCGA) Uterine Corpus Endometrial Carcinoma cohort and related cBioPortal datasets were analyzed, focusing on the insulin signaling genes INSR and PIK3CA. Results showed that INSR alterations occurred in a subset of endometrial tumors, accompanied by significantly reduced transcript expression. Altered cases were enriched in low-grade endometrioid carcinomas and were associated with improved overall survival. In contrast, PIK3CA exhibited a high frequency of activating mutations, particularly the H1047R hotspot, driving hyperactivation of downstream PI3K/AKT/mTOR signaling despite lower transcript levels. Importantly, their oncogenic activity is mediated primarily through enhanced protein phosphorylation rather than increased mRNA abundance, explaining why transcript levels alone underestimate their impact. Together, these findings indicate that dysregulation of the INSR–PIK3CA axis represents a potential molecular bridge between PCOS-related insulin resistance and endometrial carcinogenesis. Elucidating this connection may provide insight into cancer risk in women with PCOS and inform pathway-directed prevention and treatment strategies.