FP07-5 Metformin Upregulates AMPK Pathway in Humanized Aromatase Expressing ERBB2 Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP07-New Players in Hormonal Control of Breast & Prostate Cancer
Basic/Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 12:00 PM
Room 206 (Moscone Center)

Poster Board SAT-293
Hong Zhao*1, Robert T Chatterton Jr.2, John S Coon V3, David C Brooks3, Dolores Huberts3, Francesco J DeMayo4 and Serdar Ekrem Bulun1
1Northwestern Univ, Chicago, IL, 2Northwestern Univ Med Sch, Chicago, IL, 3Northwestern University, Chicago, IL, 4Baylor College of Medicine, Houston, TX
Aromatase is a key enzyme for estrogen biosynthesis. Long-term cumulative exposure to estrogen increases the breast cancer risk in women.  Recently it has been recognized that metabolic reprogramming is tumor hallmark, and an important regulator of cellular energy homeostasis that is often altered is AMP-activated protein kinase (AMPK).  Metformin, a front-line antidiabetic drug, lowers serum glucose levels via activating AMPK pathway in the liver. In vitro studies show that activated AMPK inhibits adipose tissue aromatase expression via suppression of binding of cAMP-responsive element binding protein (CREB) to aromatase promoters II/I.3, leading to decreased estrogen formation. However, there is no mouse model for study of the in vivo role of metformin on aromatase expression and carcinogenesis in mammary tissue via the AMPK pathway because mice lack aromatase expression in their mammary glands.   To address role of alteration of AMPK metabolic pathway in the most common breast cancer risk, i.e estrogen, we generated transgenic humanized aromatase (Aromhum) mice to mimic the human aromatase distribution pattern in the mouse, and crossed this mouse with an ERBB2 transgenic mouse to generate ERBB2 and Aromhum/ERBB2 (AE) mice. Fifty six percent of ERBB2 (only) mice developed mammary tumors within 6 months, as expected.  AE mice had a significantly higher (86%, p<0.05) tumor incidence at this time.  Thus, the human aromatase transgene increased the rate of mammary tumor growth in ERBB2 mice. Metformin treatment (125 mg/kg /day for 21 days) significantly decreased blood glucose levels by 35 % in AE mice over this time as compared to vehicle treatment. Immunihistochemistry demonstrated that AMPKα was expressed in both stromal and mammary epithelial cells. Phosphorylation of AMPKα was increased in breast tissues and mammary tumors of AE mice after metformin treatment, and phosphorylation of CREB, a downstream effector of the AMPK pathway, which mediates aromatase expression, was significantly decreased.  In conclusion, metformin upregulated the AMPK pathway in normal breast tissues and breast tumors of AE mice and may lead to decreased mammary aromatase expression and estrogen production, and reduced tumorigenesis.  This study provides a fundamental mechanism for testing strategies for prevention of breast cancer using the AMPK activator metformin in women with type 2 diabetes.

Nothing to Disclose: HZ, RTC Jr., JSC, DCB, DH, FJD, SEB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Avon Foundation; Lynn Sage Cancer Research Foundation