Abstract C52: Targeting the obesity/leptin link to TNBC: A breast cancer disparity problem

Triple Negative Breast Cancer (TNBC) is an aggressive cancer associated with poor prognosis and is difficult to treat. Standard therapy for TNBC includes a combination of chemotherapeutic drugs: doxorubicin (DOX), paclitaxel (TAX), and cyclophosphamide (CTX). Current epidemiological data show that obesity increases TNBC incidence, which is more relevant for African American women. Recent findings suggest that leptin (an adipokine increased in obesity) is involved in TNBC acquired drug resistance via induction of breast cancer stem cells (BCSCs). Understanding the role of obesity in TNBC is vital to the development of new and effective therapies. Chemotherapeutic drugs exhibit shortcomings that may be due to increased drug resistance, survival, proliferation, and angiogenic signal redundancy induced by leptin. Our lab has developed and tested a novel, specific inhibitor of leptin signaling, LPrA2. A pegylated derivative of LPrA2 (PEG-LPrA2) has previously shown to enhance, 68 fold, LPrA29s bioavailability in mouse breast cancer models. The objective of this study was to determine the adjuvant effects of PEG-LPrA2 on TNBC in vitro. We hypothesized that PEG-LPrA2 can serve as an adjuvant for standard TNBC chemotherapeutics. This adjuvant would allow for the reduction of chemoresistance and TNBC recurrence. It could also reduce chemotherapeutic dose and undesirable side effects associated with standard therapy for the disease. Two human TNBC cell lines were cultured: MDA-MB-231 (highly metastatic) and MDA-MB-468 (minimally invasive). Cellometer imaging technologies were used to determine S-phase progression in cells treated with PEG-LPrA2 and leptin. Flow cytometry technologies were used to determine the effects of leptin on BCSC surface markers. Additionally, in vitro toxicity of PEG-LPrA2 was tested in non-malignant mammary cells (MCF-10A) via MTT assay. Our data shows that leptin (1.2 nM, equivalent to serum levels of overweight individuals) induced S-phase progression and increased BCSC markers and the formation of TNBC tumorspheres. Remarkably, PEG-LPrA2 (1.2 nM) abrogated leptin induction of S-phase, BCSC markers, and tumorspheres. It also showed no toxicity in non-malignant cells. These results suggest leptin-signaling inhibition could be used as an adjuvant strategy for chemotherapy of TNBC. These results are most relevant for obese African American women suffering from TNBC. Citation Format: Courtney D. Dill, Adriana Harbuzariu, Tia L. Harmon, Crystal C. Lipsey, Ayobami Loye, Ruben Rene Gonzalez-Perez. Targeting the obesity/leptin link to TNBC: A breast cancer disparity problem. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C52.