Targeting Breast Cancer Stem Cells in Triple-Negative Breast Cancer
Abstract
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-2/Notch 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 drugs(sunitinib) 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1003304
Entities
People
- Ruben R. Gonzalez-perez
Organizations
- Morehouse School of Medicine