The truncated somatostatin receptor sst5TMD4 stimulates the angiogenic process and is associated to lymphatic metastasis and disease-free survival in breast cancer patients

// Manuel D. Gahete 1, 2, 3, 4, * , David Rincon-Fernandez 1, 2, 3, 4, * , Mario Duran-Prado 2 , Marta Hergueta-Redondo 5 , Alejandro Ibanez-Costa 1, 2, 3, 4 , Alejandro Rojo-Sebastian 6 , Francisco Gracia-Navarro 1, 2, 3, 4 , Michael D. Culler 7 , Oriol Casanovas 8 , Gema Moreno-Bueno 5 , Raul M. Luque 1, 2, 3, 4, ** , Justo P. Castano 1, 2, 3, 4, ** 1 Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain 2 Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain 3 Reina Sofia University Hospital (HURS), Cordoba, Spain 4 CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Cordoba, Spain 5 Department of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomedicas “Alberto Sols” (CSIC-UAM), IdiPAZ, MD Anderson Internacional Foundation, Madrid, Spain 6 Pathology Deparment, MD Anderson Cancer Center, Madrid, Spain 7 IPSEN Bioscience, Cambridge, Massachusetts, USA 8 Tumor Angiogenesis Group, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain * These authors contributed equally to the study and should be considered co-first authors ** These authors co-directed the study and should be considered co-senior authors Correspondence to: Justo P. Castano, email: justo@uco.es Raul M. Luque, email: raul.luque@uco.es Keywords: somatostatin receptor, sst5TMD4, breast cancer, angiogenesis, VEGF Received: May 09, 2016     Accepted: July 19, 2016     Published: August 05, 2016 ABSTRACT The truncated somatostatin receptor sst5TMD4 is associated with poor prognosis in breast cancer and increases breast cancer cell malignancy. Here, we examined the cellular/molecular mechanisms underlying this association, aiming to identify new molecular tools to improve diagnosis, prognosis or therapy. A gene expression array comparing sst5TMD4 stably-transfected MCF-7 cells and their controls (empty-plasmid) revealed the existence of profound alterations in the expression of genes involved in key tumoral processes, such as cell survival or angiogenesis. Moreover, sst5TMD4-overexpressing MCF-7 and MDA-MB-231 cells demonstrated increased expression/production of pro-angiogenic factors and enhanced capacity to form mammospheres. Consistently, sst5TMD4-expressing MCF-7 cells induced xenografted tumors with higher VEGF levels and elevated number of blood vessels. Importantly, sst5TMD4 was expressed in a subset of breast cancers, where it correlated with angiogenic markers, lymphatic metastasis, and reduced disease-free survival. These results, coupled to our previous data, support a relevant role of sst5TMD4 in the angiogenic process and reinforce the role of sst5TMD4 in breast cancer malignancy and metastatic potential, supporting its possible utility to develop new molecular biomarkers and drug therapies for these tumors.