8033 Pioglitazone Regulates Metabolic Comorbidity of Breast Cancer Endocrine Therapy

Abstract Disclosure: N.S. Thomas: None. The survival rates of women with estrogen receptor-positive (ER+) breast cancer are typically higher when compared to those with ER-negative and triple-negative (TN) breast cancers. This remarkable progress in survivorship during past decades can be attributed to advancements in treatment and enhanced early detection. However, the prevalence of weight gain and increased risk (30%) of type 2 diabetes (T2D) have been observed in breast cancer survivors treated with tamoxifen (TAM) or aromatase inhibitors, particularly in women with elevated BMI. Furthermore, the T2D risk is 19% higher in tamoxifen-treated women compared to matched individuals without cancer, suggesting a potential association between endocrine therapy and diabetes in breast cancer survivors. Our recent research determined that in female obese mice, endocrine therapy disrupted metabolic homeostasis causing glucose intolerance and ectopic fat deposition associated with adipocyte hypertrophy and depletion of adipocyte progenitor cells. We hypothesized that ER signaling maintains adipocyte progenitors to promote healthy adipose expansion during weight gain, which is disrupted with endocrine therapy. Supplementation of pioglitazone, a thiazolidinedione class of drug and agonist for the peroxisome proliferator-activated receptor-γ to endocrine therapy-treated mice promoted proliferation of the adipocyte precursor population within two weeks of treatment. Though pioglitazone did not significantly affect body weight, its protective effect over endocrine therapy was reflected in maintaining estrogen receptor expression, improved insulin sensitivity, reduced subcutaneous adipocyte diameter, decreased visceral fat, diminished liver triglycerides, and less hepatic steatosis. Flow cytometry analysis with mouse adipocyte precursor cells showed that progenitors were greater with either estrogen or pioglitazone treatment and lower after ER antagonism. The loss of progenitor phenotype in endocrine therapy-treated cells was rescued by pioglitazone intervention. The results of this study may help us better understand and prevent the risk for diabetes in breast cancer survivors. Presentation: 6/2/2024