Effects of obesity on anastrozole response in a mouse model of postmenopausal breast cancer.
Authors: DeAngel R , Tolstykh O , Nameer K , Jayarajan R , Perkins S , Tekmal R , DeGraffenried L , Hursting S 
Published: December 2010

Abstract
Abstract #1146
Background: The prevalence of obesity, an established breast cancer risk factor for postmenopausal women, has risen rapidly in the US in recent decades. The majority of postmenopausal breast tumors are estrogen receptor-α positive (ER-α+) and responsive to the mitogenic effects of estrogen. Tamoxifen, a selective estrogen receptor modulator, has been the endocrine agent of choice for the treatment and prevention of ER-α+ breast cancer. Unfortunately, resistance to tamoxifen develops in the majority of cases. Akt activation in breast tumors is associated with poor prognosis and resistance to tamoxifen and other forms of endocrine therapy. Akt activation in the mammary epithelium is also enhanced by obesity, possibly due to elevated growth factor and hormone levels known to activate the PI3K/Akt/mTOR pathway. Aromatase inhibitors, such as anastrozole, are emerging as the treatment of choice for the postmenopausal patient, yet little is known as to how obesity may modulate response to these agents. In this study we examined the effect of obesity on tumor growth response to anastrozole and local tumor aromatase expression. We also assessed the correlation between obesity, Akt activation and tumor growth.&#x2028; Methods: To mimic postmenopausal obesity, ovariectomized C57BL/6 mice (n=80) were randomized to a control diet (10 Kcal% fat; ∼10.2 kcal/day) or a diet-induced obesity (DIO) regimen (60 Kcal% fat; ∼14.4 kcal/day). After 14 wk on the diets mice were injected with isogenic MMTV-Wnt-1 mammary tumor cells (5x104 cells/mouse) in the 4th mammary fat pad. After tumors became palpable mice were injected with the AI anastrozole (10 μg/day s.c.) or vehicle control (0.3% hydroxypropylcellulose) for 4 wk. Serum leptin and resistin were measured at the end of the study, RT-PCR and western blot analyses were used to determine aromatase gene expression and total and phosphorylated protein levels in the tumors.&#x2028; Results: Mice on the DIO regimens were significantly heavier (39.2 g ±0.7) than controls (29.7 g ±1.23), with significantly higher circulating levels of the obesity-related adipokines leptin and resistin. Tumors from DIO mice, relative to controls, displayed increased aromatase expression. Anastrozole had no effect on food consumption or body weight but intriguingly increased aromatase expression in tumors from both control and DIO mice. Importantly, DIO mice, relative to controls, were much less responsive to the tumor inhibitory effect of anastrozole. Akt protein expression correlated positively with tumor weight, regardless of dietary or hormonal treatment.&#x2028; Conclusion: In the context of postmenopausal breast cancer, our results suggest that obese mice compared to controls are less responsive to the effects of anastrozole on tumor growth and that aromatase expression in tumors is higher in obese mice regardless of anastrozole treatment. We also found a strong correlation between Akt activation and tumor growth, irrespective of diet or hormonal treatment.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1146.