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Targeting Breast Cancer Stem Cells in Triple-Negative Breast Cancer

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Morehouse School of Medicine Atlanta United States

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Our central hypothesis is that in overweight and obese triple negative breast cancer TNBC patients the elevated levels of leptin increase drug resistance through induction of breast cancer stem cells BCSC. Leptin secreted by adipose or TNBC activates VEGFR-2Notch axis increasing tumor growth, angiogenesis and BCSC, which induce metastasis and drug resistance. Leptin induces tumor angiogenesis by mechanisms not completely understood. We found for the first time that leptin induces Notch expression in endothelial cells via trans-activation of VEGFR, which was independent from VEGF and, linked to increased cell proliferation, and the development of angiogenic features. A novel leptin signaling inhibitor conjugated to nanoparticles IONP-LPrA2 has been characterized. IONP-LPrA2increases the effectiveness of several chemotherapeutic doxorubicin, cisplatin, paclitaxel and angiogenic drugssunitinib on TNBC cell lines. Data obtained suggest that IONP-LPrA2 has potential beneficial effects for TNBC patients, specifically those that are obese and show the higher leptin levels and, poorer outcome. IONP-LPrA2 may increase the efficacy of chemotherapeutics in vivo and, allow reduction of dose and side effects. IONP-LPrA2 adjuvant used alone or with chemotherapeutics will be applied to syngeneic obese mice hosting TNBC. Investigations on IONPLPrA2therapeutic potential and the elucidation of the molecular mechanisms by which leptin-induces BCSC survival and increases drug resistant in obese contexts may identify new targets for therapeutic intervention, for the hard-to treat TNBC, which has not targeted therapies.

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Technical Report,30 Sep 2014,29 Sep 2015



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