Abstract P3-11-02: Weight maintenance initiated at midlife reduces mammary tumor incidence but metformin treatment does not mimic the effect
Authors: Cleary MP , Mizuno NK , Yang D-Q , Liao J , Grossmann ME 
Published: May 2016

Abstract
Weight gain and/or obesity are now considered to be risk factors for the development of postmenopausal breast cancer. Thus, weight loss and/or maintenance resulting from calorie restriction (CR) is recommended however success rates are infrequent. Metformin (MET) is a safe and effective treatment for type 2 diabetes mellitus and its use has been linked to reduced breast cancer incidence and mortality in comparison to other forms of diabetes treatments. Interestingly, MET's mechanism of action is considered to be similar to CR. The goal of the present investigation was to directly compare the effect of CR implemented at midlife with the administration of metformin on the development of mammary tumors (MT) in a relevant mouse model. Further, since these interventions would likely be used by obese women we studied both lean and obese mice. Female MMTV-TGF-α mice which develop MTs in the second year of life were fed ad libitum (AL) either a low fat (LF) (10.2% by calories) diet or a moderately high fat (HF) (33.5% by calories) diet from 10 until 30 weeks of age. At 30 weeks the mice on each diet were divided into AL, MET (250 mg/kg/bw/day) or CR (25% reduction in calories) subgroups and then followed until 90 weeks of age. HF-AL and HF-Met mice were significantly heavier that the other 4 groups whose weights were similar. The survival curves had an overall P value of P&lt;0.0001 with LF-CR having the best survival of 100% while the HF-AL and HF-Met had the poorest survival with rates of 68% and 63% respectively. HF-CR mice had a significantly better survival rate compared to HF-AL and HF-Met (P&lt;0.0001 for both). MT incidence (histologically confirmed) was significantly reduced in LF-CR (6%) compared to all other groups (45%-69%) (Chi-squared analysis). Tumor incidence in the HF-CR group (51%) was reduced compared to HF-AL (69%) and HF-Met (60%) mice but not significantly different due to adjustment for multiple comparisons, although the HF-CR vs HF-AL comparison was P&lt;0.02. However, when the incidence rate for tumors detected by palpation prior to euthanasia was examined LF-CR mice did not have any MTs although the palpable incidence rates were not significantly different due to the need for multiple comparisons (LF-CR vs LF-AL was P&lt;0.0097). The HF-CR group had significantly reduced palpable MT prior to euthanasia as compared to both HF-AL and the HF-Met (P&lt;0.0002 and P&lt;0.0001 respectively). Total tumor weight, grade and multiplicity were also examined for the effects of weight maintenance and MET. Presently the role of the AMPK pathway in these effects and serum measurements are being determined. In conclusion, the results to date indicate that weight maintenance during midlife can have a significant impact in delaying MT formation regardless of body weight status although the effects of MET are less dramatic.
Supported by NIH-NCI CA157012, The Hormel Foundation and Paint the Town Pink.
Citation Format: Cleary MP, Mizuno NK, Yang D-Q, Liao J, Grossmann ME. Weight maintenance initiated at midlife reduces mammary tumor incidence but metformin treatment does not mimic the effect. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-11-02.