In vitro conditions that mimic diabetes and obesity enhance proliferation of both non-tumorigenic and malignant breast epithelial cells through increased leptin signaling and activation of PI3K and AKT signaling pathways

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 292-302-Breast & Prostate Cancer
Basic/Translational
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-298
Rebecca Lopez*1, Pamela Agullo2, Arunkumar Arumugam3, Riya Joseph2, Kanika Monga2, Christina Gutierrez2, Sushmita B Nandy3, Thiyagarajan Boopalan4 and Rajkumar Lakshmanaswamy5
1Texas Tech University Health Sciences, El Paso, TX, 2Texas Tech University Health Sciences Center, El Paso, TX, 3Texas Tech University Health Sci, El Paso, TX, 4Texas Tech Univ, El Paso, TX, 5Texas Tech Univ Health Sci Ctr, El Paso, TX
Introduction: Diabetes and obesity, which are increasing globally at alarming rates, increase the risk of breast cancer and also result in more aggressive disease once breast cancer develops. Breast cancer is the most common cancer affecting women worldwide and incidence continues to increase. While many advances have been made, the precise mechanisms by which diabetes and obesity increase breast cancer risk and severity are still not fully understood. Therefore, it is critical to elucidate the precise mechanisms behind these observations. 

Methods:  Non-tumorigenic MCF10A breast epithelial cells and malignant MCF7 and MB-MDA-231 breast epithelial cells were treated with increasing glucose concentrations to mimic physiologically normal (5.5mM) and diabetic (10mM - 25mM) levels of glucose. In addition, cells were treated with physiologically normal and abnormal levels of leptin and adiponectin that mimic lean and obese conditions under both normal and diabetic glucose levels. The effects of these treatments on cell proliferation and intracellular signaling were assessed at 24hr, 48hr, and 72hr. MTS or crystal violet assays were used to monitor cell proliferation. Protein immunoblotting was used to assess key downstream signaling intermediates.
Results: Diabetic and obese conditions significantly increased levels of cell proliferation in both non-tumorigenic and malignant breast cells.  Diabetic conditions alone induced leptin signaling in all cells based on increased levels of leptin receptor and differential regulation of downstream leptin signaling targets (SHP2, AgRP, MC4R, and LKB1).  Interestingly, physiologic levels of adiponectin found in lean individuals inhibited cell proliferation more robustly under diabetic glucose levels and had a less dramatic effect under normal glucose levels.  Moreover, diabetic and obese conditions—both individually and in combination—resulted in increased activation of IGF1R, PI3K, AKT, and IRS1/2.
Conclusions: To our knowledge, we show for the first time that diabetic glucose levels alone (in the absence of hyperleptinemia or hyperinsulinemia) enhance leptin-receptor signaling in breast epithelial cells. This implicates leptin-receptor signaling in the pathogenesis of diabetes in both normal and malignant cells. Key signaling intermediates in this pathway may be useful targets for prevention and treatment of diabetes, obesity, and ultimately breast cancer.  In addition, we believe we show for the first time that the inhibitory effects of adiponectin on cell proliferation are highly dependent on glucose levels and the etiology behind this observation warrants further investigation.

Nothing to Disclose: RL, PA, AA, RJ, KM, CG, SBN, TB, RL

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