Abstract
Abstract Background: Obese patients develop more frequently triple negative breast cancer (TNBC) that has not target therapy and are commonly treated with chemotherapeutics. Leptin, whose levels are elevated in obesity, can induce TNBC proliferation, angiogenesis and resistance to chemotherapeutics. An antagonist for leptin receptor OB-R, leptin peptide receptor antagonist 2 (LPrA2), has been shown to block leptin signaling and decrease tumor progression. LPrA2 also countervails leptin induced resistance to chemotherapeutic agents. We used pegylation or iron oxide nanoparticle (IONPs) as adjuvants to increase LPrA2 solubility, stability and effectiveness. Hypothesis: Conjugated LPrA2 will decrease TNBC cells proliferation, expression of leptin target molecules and tumorigenesis. Methods: Human TNBC and murine breast adenocarcinoma derived cell line E0771 (progesterone and HER2 receptor negative) were used. The E0771 cell line was generated from an estrogen receptor positive (ER+) mammary adenocarcinoma isolated from a C57BL/6J mouse. E0771 was made insensitive to estrogen by treatment with drug Tamoxifen (TAM) mimicking TNBC. To specifically assess the role of RBP-Jk (CBS/CSL, an essential transcription factor for Notch signaling) the CRISPR/Cas9 system was used to disrupt RBP-JK gene expression in both wild-type and TAM treated E0771 cells. Cells were treated with chemotherapeutics (Paclitaxel, Doxorubicine, Ciclophosphamide) in presence of leptin and LPrA2-conjugates. The expression of leptin-targeted molecules, Breast Cancer Stem Cells (BCSC) and EMT markers were analyzed after cell treatment. Results: Chemotherapeutics effects on proliferation, survival and molecular markers were modified by the addition of LPrA2-conjugates. Notch molecules (receptors and ligands) were downregulated by LPrA2 treatment. Conclusion: The current data indicate that Leptin inhibition could be used as an adjuvant for chemotherapeutic treatments in TNBC patients. LPrA2-conjugates could increase the efficacy of chemotherapy. Acknowledgements: This work was partially supported by the National Institute of Health and National Cancer Institute Grant U54 CA118638, NIH/SBIR 1R41CA183399-01A1, and DOD Idea Award BC W81XWH-13-1-0382 to RRGP; and facilities, and support services at Morehouse School of Medicine (NIH RR03034 and 1C06 RR18386) and NIH/NCRR grant 1G12RR026250-03. Citation Format: Antonio Rampoldi, Adriana Harbuzariu, Tia L. Harmon, Ruben R. Gonzalez-Perez. Novel adjuvants in triple negative breast cancer chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1006.
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