Abstract
Abstract Introduction: Triple negative breast cancer (TNBC) is a particularly aggressive form of the disease whose incidence is disproportionate in obese African American and Latina women. TNBC is commonly associated with acute early onset, poor survival and acquired drug-resistance. Obesity, characterized by high levels of leptin, is frequently found among these ethnic groups. We hypothesize that intact leptin-Notch-Wnt signaling crosstalk affects the development of drug-resistance in TNBC. Objective: To determine whether leptin signaling induces Notch/Wnt pathway crosstalk, decreasing the effectiveness of cisplatin in TNBC cells. Materials & Methods: TNBC cells (MDA MB 231 and HCC1806) and ER+ MCF-7 (as control) were treated with pharmacological doses of leptin and agonists of the Notch and Wnt pathways JAG1-17 mer peptide and Wnt-1, respectively. In addition, the cells were challenged with the leptin receptor, Notch pathway, and Wnt pathway antagonists LPrA2, DAPT, and Wnt-1 respectively. The impact of these molecules on cisplatin anti-cancer effects was also determined. Activation of Wnt (total/pβ-catenin), expression of Notch (Notch 1-4 and JAG1/Dll-4 and targets: survivin/Hey2), cell proliferation and apoptosis were determined by Western blot and flow cytometry. β-catenin levels were also investigated by immunofluorescence. We also determined the impact of the inhibition of leptin signaling (via LPrA2) on the expression of Wnt and Notch in DMBA-induced breast cancer from DIO (diet-induced obese) mice. Results: We found that leptin increased the levels of β-catenin mainly in TNBC cells. Similarly, inhibition of leptin signaling decreased Wnt/Notch expression in DMBA/DIO-breast cancer. Interestingly, leptin increased expression of Notch and attenuated the detrimental effects of cisplatin on breast cancer cells. Wnt-1 affected Notch levels but its effects were less pronounced. Conclusions: Leptin is able to induce the Notch and Wnt signaling pathways in breast cancer. Cisplatin effects were attenuated by leptin in TNBC probably through its crosstalk with Wnt and Notch signaling pathways. These results are particularly relevant for TNBC and obese patients, and suggest that leptin inhibition could be useful in increasing the chemotherapeutic effectiveness in TBNC by disrupting leptin-Wnt-Notch crosstalk. [This work was supported in part by NIH/NCI1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1 and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP); CREDO (MSCR) 2R25RR017694-06A1 (to L.S.C); NIH/NIGMS R25 GM058268 and NCRR 5P20RR11104 (to T.Z.M); and facilities and support services at MSM (NIH RR03034 and 1C06 RR18386)]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 785. doi:1538-7445.AM2012-785
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