Background

Estrogen receptor (ER) positive breast cancer is diagnosed in >150,000 women annually. Patients receive drugs to block ER (Tamoxifen) or lower estrogen levels (aromatase inhibitors), for 5-10 years after diagnosis. Breast cancer survivors have an elevated incidence of hepatic steatosis and type 2 diabetes (T2D) compared to women who were not treated for cancer, with the greatest risk occurring after Tamoxifen treatment. Up to 48% of T2D cases in breast cancer survivors are attributable to their prescribed therapies; however, the underlying mechanisms are not known. We hypothesized that obesity, which increases the risk for breast cancer, worsens metabolic outcomes associated with Tamoxifen or estrogen deprivation.

Methods

Lean or diet-induced obese female mice were treated with estrogen (E2), E2+Tamoxifen (TAM) or estrogen deprivation (ED) therapy.

Results

ED promoted weight and fat gain regardless of adiposity, but only impaired insulin sensitivity in obese females, measured by fasting glucose and insulin. In contrast, TAM worsened metabolism only in the obese, increasing weight and fat gain, and independently impairing insulin sensitivity. Interval exercise training restored metabolic health in obese mice during ED but not TAM treatment. Analysis of subcutaneous adipose tissue showed persistent adipocyte hypertrophy in obese TAM-treated mice and a significant reduction in adipocyte progenitor cells, suggesting a failure of healthy adipose tissue expansion. Consistent with this, we observed hepatic lipid deposition in obese TAM and ED treated females, which was only prevented by exercise in the ED group.

Conclusions

This is the first preclinical model of breast cancer therapy that recapitulates observations made in women. In the context of obesity, TAM causes insulin resistance, prevents adipocyte expansion, and leads to fatty liver and unlike EWD, these effects are not reversed with exercise therefore treatments need to be developed for women taking TAM to prevent T2D.