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

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Title: Impact of obesity on MMTV-Wnt-1 mammary cancer : role of the insulin-like growth factor-1 (IGF-1)/Akt/mTOR pathway
Author: De Angel, Rebecca Elena
Abstract: 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 .
URI: http : / /hdl .handle .net /2152 /ETD -UT -2010 -12 -2101
Date: 2011-02-02

Citation

Impact of obesity on MMTV-Wnt-1 mammary cancer : role of the insulin-like growth factor-1 (IGF-1)/Akt/mTOR pathway. Doctoral dissertation, University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /ETD -UT -2010 -12 -2101 .

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