PR inhibition stimulates G6PD expression to enhance malignancy in luminal breast cancer.

Luminal breast cancer is the most prevalent and prognostic subtype of breast cancer. However, it has been reported that luminal breast cancer patients with lower progesterone receptor (PR) expression are associated with poor survival outcomes. Nevertheless, there is insufficient evidence linking PR expression to an aggressiveness of luminal breast cancer. Based on our previous studies showing an inverse correlation between PR and standardized uptake value (SUV) on [18 F] fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to identify a potential link between PR expression and glucose metabolism, particularly the pentose phosphate pathway (PPP). To investigate it, we performed a single cell RNA sequencing (scRNA-seq) analysis using published dataset. Interestingly, the analysis revealed that specific epithelial cells with both increased proliferation activity and decreased PR expression, which increased activity of the PPP and glucose-6-phosphate dehydrogenase (G6PD) expression. To verify these findings, we silenced PR expression in the luminal breast cancer cell lines, MCF7 and T47D, which led to accelerated proliferation and PPP activity with G6PD expression. We hypothesized that PR knockdown (KD) increases breast cancer aggressiveness by boosting glucose utilization with PPP activity. Importantly, treatment with G6PD inhibitor (G6PDi), a G6PDi reduced aggressiveness of PR KD cancer cells. These findings suggest that targeting G6PD could be a promising therapeutic strategy to suppress the aggressiveness of luminal breast cancer, using low PR expression as a biomarker.