Association between GPX4 and HMGCR gene expression and cell proliferation in atypical hyperplasia of the breast

Abstract

Aim: Using a dataset available from the NCBI Gene Expression Omnibus Repository, this in silico study investigated the differential expression of GPX4, the gene coding for the detoxifying enzyme glutathione peroxidase paired samples of AH (atypical hyperplasia) and corresponding histologically normal (HN) tissue from 17 women with AH and in four samples of normal breast tissue used as controls. Methods: The study focused on the genes (HMGCR, FDPS, FDFT1, and GGPS1) involved in the production and breakdown of isopentenyl-diphosphate, a key component for GPX4 biosynthesis. It also explored the connection between the expression of GPX4 and the genes (CCND1, CDK4, CDK6, and CDKN1B) associated with the cyclin D1-CDK4/6 complex. Results: Compared to HN tissue, AHs exhibited higher levels of GPX4 and HMGCR, supporting the functional connection between GPX4 synthesis and isopentenyl-diphosphate production. Additionally, AHs showed elevated levels of CCND1 and CDKN1B and decreased levels of CDK6. Compared to normal breast tissue, HNs showed similar alterations, suggesting that ferroptosis escape and uncontrolled proliferation are early molecular events in the neoplastic transformation. Compared to HN tissue, AHs also expressed high levels of GGPS1, a downstream gene of HMGCR, which leads to the synthesis of geranylgeranyl-diphosphate, a molecule essential for the post-translational modification of the proteins involved in the regulation of the Hippo signaling pathway. Conclusions: Although very preliminary, present results seem to suggest that blocking the mevalonate pathway by statins might, on the one hand, prevent AHs from escaping ferroptosis through depleting isopentenyl-diphosphate and, on the other hand, inhibit cell proliferation by controlling the Hippo pathway.

Keywords

• atypical hyperplasia
• gpx4
• hmgcr
• ferroptosis
• cell proliferation