CIDIE   24052
CENTRO DE INVESTIGACION Y DESARROLLO EN INMUNOLOGIA Y ENFERMEDADES INFECCIOSAS
Unidad Ejecutora - UE
artículos
Título:
Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC.
Autor/es:
GÜTTLEIN LN, BENEDETTI LG, FRESNO C, SPALLANZANI RG, MANSILLA SF, ROTONDARO C, RAFFO IRAOLAGOITIA XL, SALVATIERRA E, BRAVO AI, FERNÁNDEZ EA, GOTTIFREDI V, ZWIRNER NW, LLERA AS, PODHAJCER OL.; GÜTTLEIN LN, BENEDETTI LG, FRESNO C, SPALLANZANI RG, MANSILLA SF, ROTONDARO C, RAFFO IRAOLAGOITIA XL, SALVATIERRA E, BRAVO AI, FERNÁNDEZ EA, GOTTIFREDI V, ZWIRNER NW, LLERA AS, PODHAJCER OL.
Revista:
MOLECULAR CANCER
Editorial:
BIOMED CENTRAL LTD
Referencias:
Lugar: Londres; Año: 2017 vol. 15 p. 304 - 316
ISSN:
1476-4598
Resumen:
Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice. A comprehensive study including global transcriptomic analysis followed by biological validations confirmed that SPARC induces primary tumor growth by enhancing cell cycle and by promoting a COX-2-mediated expansion of myeloid-derived suppressor cells (MDSC). The role of SPARC in metastasis involved a COX-2-independent enhancement of cell disengagement from the primary tumor and adherence to the lungs that fostered metastasis implantation. Interestingly, SPARC-driven gene expression signatures obtained from these murine models predicted the clinical outcome of patients with HER2-enriched breast cancer subtypes. In total, the results reveal that SPARC and its downstream effectors are attractive targets for antimetastatic therapies in breast cancer.Implications: These findings shed light on the prometastatic role of SPARC, a key protein expressed by breast cancer cells and surrounding stroma, with important consequences for disease outcome