Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC

PODHAJCER OL; GOTTIFREDI V; SALVATIERRA E; ZWIRNER NW; LLERA AS; MANSILLA SF; BRAVO AI; FERNÁNDEZ EA; BENEDETTI LG; ROTONDARO C; RAFFO IRAOLAGOITIA XL; LLERA AS; FRESNO C; SPALLANZANI RG; FERNÁNDEZ EA; PODHAJCER OL; GÜTTLEIN LN; RAFFO IRAOLAGOITIA XL; GOTTIFREDI V; ZWIRNER NW; SALVATIERRA E; SPALLANZANI RG; BRAVO AI; MANSILLA SF; GÜTTLEIN LN; ROTONDARO C; BENEDETTI LG; FRESNO C

MOLECULAR CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2017

1541-7786

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