Objective Breast cancer affects 1 in 8 women and is the chief cause of female cancerdeaths in the EU. Early detection continues to improve survival, but prognosisworsens significantly after metastasis. Metastasis and chemoresistance are linkedphenomena, but the molecular basis is unknown. The evidence suggests a role forCaveolin1 (Cav1): i) Cav1 mediates biomechanical remodelling of the extracellularmatrix by cancer-associated fibroblasts (CAFs), promoting invasion (host labpublications); ii) Cav1 is involved in drug/radiation resistance, and the Cav1β isoformmight regulate resistance of breast tumour cells (TCs) to paclitaxel (literature); iii)The Cav1 content of breast-TC exosomes correlates with metastatic potential (ourpreliminary data).We propose that acquisition of invasiveness by TCs is related to their releaseof Cav1-containing exosomes. Cav1-activated CAFs then increase matrix stiffness,providing the appropriate milieu for TC metastasis. The N-terminally curtailed Cav1βprecludes chemotherapy-induced tyr14 phosphorylation, preventing Bcl2 binding andconferring resistance. Cav1 α and β might thus balance the interplay between TCsand CAFs during tumour progression.To integrate these data and verify our hypothesis, we propose state-of-the-art approaches andmultidisciplinary strategies, ranging from cell biology to animalmodels and clinical screening studies. As side products, tools of interest will beproduced such as a new antibody to Cav1β, useful for stratifying patients accordingto their likely benefit from paclitaxel therapy, and a new Cav-/- mouse generated byZFN targeting in the NSG strain, which promises a method for conducting humantransplants in genetically modified animal models.The complementary expertise of fellow and host lab, coupled with theexcellent scientific environment at the host institute, provide a firm basis for successof this ambitious but sound proposal, thus fostering the fellow’s progress toindependence. Fields of science natural sciencesbiological sciencescell biologymedical and health sciencesclinical medicineoncologybreast cancer Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2013-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Call for proposal FP7-PEOPLE-2013-IEF See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.) Address Calle melchor fernandez almagro 3 28029 Madrid Spain See on map Region Comunidad de Madrid Comunidad de Madrid Madrid Activity type Research Organisations Administrative Contact Luz Mª Garcia (Ms.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution € 230 036,60
