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

GUTTLEIN, LEANDRO N.; BENEDETTI, LORENA G.; FRESNO, CRISTOBAL; SPALLANZANI, RAUL G.; MANSILLA, SABRINA F.; ROTONDARO, CECILIA; IRAOLAGOITIA, XIMENA L. RAFFO; SALVATIERRA, EDGARDO; BRAVO, ALICIA I.; FERNANDEZ, ELMER A.; GOTTIFREDI, VANESA; ZWIRNER, NORBERTO W.; LLERA, ANDREA S.; PODHAJCER, OSVALDO L.

MOLECULAR CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Año: 2017 vol. 15 p. 304 - 316

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.