Abstract 5643: Role of leptin-induced Notch-Wnt crosstalk in proliferation/survival of triple negative breast cancer cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Obese African American and Latina women show the high mortality rate linked to triple negative breast cancer, TNBC. The disease is commonly detected at more advance degree and associated with resistance to common therapeutic treatments. Obesity, characterized by high levels of leptin, has consistently been associated with many different cancers including breast cancer. We hypothesize that leptin signaling is instrumental in the increased proliferation and survival of breast cancer cells, which is mediated through a crosstalk between the Notch and Wnt signaling pathways. We further hypothesized that these leptin actions are more evident in TNBC cells. Objective/Methods: The effects of leptin-Notch-Wnt crosstalk on the proliferation and survival (MTT-Vybrant assay and Annexin V-flow cytometry) of breast cancer cells responsive to estrogen (MCF-7 and T47D) and TNBC (MDA-MB231 and HC1806) were investigated. The cells were treated with agonists and inhibitors of leptin-Notch-Wnt axis [i.e., leptin, Wnt1, JAG1/14-mer peptide and leptin peptide receptor antagonist 2 (LPrA2), g-secretase inhibitor and Wif]. The expression of Notch and Wnt signaling components (ligands/receptors) and levels of cyclin D1 and myc were also determined via western blot and real-time RT-PCR. In a series of experiments the cells were treated with chemotherapeutic drugs, doxorubicin and cisplatin plus leptin and the activation of caspase 3, levels of Bcl-2 and, the drug resistance marker (multidrug resistance-associated protein 1, ABCC1/MRP1) were determined using as control the etoposide resistant MCF-7/VP cell line. The relative expression of leptin, Notch and Wnt systems in breast cancer tissue arrays (n=150; Pantomics) was also investigated. Results: Leptin induced significant increase of TNBC cell proliferation, cyclin D1, bcl-2, ABCC1 and Notch/Wnt axis. Leptin also decreased the anti-cancer effects of doxorubicin and cisplatin, which were related to leptin upregulation on Notch-Wnt crosstalk. HScore analyses of breast cancer tissue arrays showed significant correlation of the expression of leptin-targeted proteins (Notch and Wnt) in breast cancer tissues. These results suggest that leptin can induce the crosstalk between Notch and Wnt and breast cancer progression. Conclusions: Targeting leptin-Notch-Wnt signaling axis could be a new strategy to treat and/or prevent breast cancer. The inhibition of leptin signaling could be a promising new way to target the most deadly TBNC, especially in obese patients. Acknowledgments: This work was supported by NIH/NCI 5SC1CA138658-04, Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP), NIH/2G12RR003034-26 and U54 MSM/TU/UAB Cancer Center Partnership, and NIH/NIGMS R25 GM058268. This research was also supported, in part, facilities and support services at Morehouse School of Medicine (NIH 1C06 RR18386). Citation Format: Tanisha Z. McGlothen, Corey Gillespie, Krysta Greenleaf, Movado Long, Laronna S. Colbert, Gary L. Sanford, Ruben R. Gonzalez-Perez. Role of leptin-induced Notch-Wnt crosstalk in proliferation/survival of triple negative breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5643. doi:10.1158/1538-7445.AM2013-5643