Impact of obesity on MMTV-Wnt-1 mammary cancer : role of the insulin-like growth factor-1 (IGF-1)/Akt/mTOR pathway

Obesity increases breast cancer risk and progression in postmenopausal women. The Akt/mTOR signaling pathway is activated in tumors in response to increased levels of obesity-related growth factors, including insulin-like growth factor (IGF)-1. Hence, we evaluated energy balance modulation as a mechanism for breast cancer prevention through modulation of Akt/mTOR. Studies suggest that dietary calcium can decrease weight gain, although an exact mechanism is not yet identified. Therefore, we investigated the effects of low-fat (10 kcal % fat) or high-fat (45 kcal % fat) diets containing either calcium phosphate (dairy) or calcium carbonate (supplement) on body weight in ovariectomized (OVX) C57BL/6 mice to determine if dietary calcium could overcome the effects of a high-fat diet. We showed that dairy decreased body weight, with no effect on food consumption. However, it is not known if restoration of normal weight can reverse mammary tumor progression and/or Akt/mTOR pathway activation. To evaluate this, mice were fed a control diet, a calorie restricted regimen, or a diet-induced obesity (DIO) regimen for 17 weeks, after which the DIO mice were switched to the control diet, and this resulted in a 20% weight loss and mice of equal weight to control mice. MMTV-Wnt-1 mammary tumor cells were orthopically injected at week 20, following weight loss. At week 22, mice began placebo or RAD001, an mTOR inhibitor, treatment by oral gavage. Tumor growth and Akt/mTOR signaling were enhanced in formerly obese mice, despite reduction in weight, adiposity and serum hormone levels. RAD001 decreased tumor growth in the CR and control group, but was less effective in the formerly obese mice. In an additional study, we added a DIO gourp which was not switched to the control diet, and found that circulating IGF-1 levels remained significantly elevated in formerly obese mice relative to control and were comparable to levels in the DIO mice. We found that the mechanism of tumor progression was through enhanced Akt/mTOR signaling in both obese and formerly obese mice. Based on the Akt/mTOR activation in MMTV-Wnt-1 tumor growth and progression, we next investigated the anticancer effects of ursolic acid (UA), a pentacyclic triterpene. It was previously shown that UA can affect Akt signaling. Our results showed that UA was effective decreasing tumor growth and Akt/mTOR signaling. Taken together, our findings show that the growth-enhancing effects of obesity on mammary tumor may persist even after weight loss and suggest that a combination of dietary and pharmacologic interventions targeting IGF-1/Akt/mTOR may be an effective strategy in the treatment of postmenopausal breast cancer.