Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC

• Published in: Molecular cancer research Vol. 15; no. 3; pp. 304 - 316
• Main Authors: Güttlein, Leandro N., Benedetti, Lorena G., Fresno, Cristóbal, Spallanzani, Raúl G., Mansilla, Sabrina F., Rotondaro, Cecilia, Raffo Iraolagoitia, Ximena L., Salvatierra, Edgardo, Bravo, Alicia I., Fernández, Elmer A., Gottifredi, Vanesa, Zwirner, Norberto W., Llera, Andrea S., Podhajcer, Osvaldo L.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.03.2017
• Subjects: Animal models; Animals; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell cycle; Cell Growth Processes - physiology; Cell Line, Tumor; Colonization; Cyclooxygenase-2; ErbB-2 protein; Female; Gene expression; Glycoproteins; Humans; Implantation; Lungs; Mammary Neoplasms, Experimental - enzymology; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; MCF-7 Cells; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Osteonectin; Osteonectin - genetics; Osteonectin - metabolism; Prognosis; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Signatures; Stroma; Suppressor cells; Treatment Outcome
• DOI: 10.1158/1541-7786.MCR-16-0243-T
• ISSN: 1541-7786; 1557-3125

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. Mol Cancer Res; 15(3); 304–16. ©2016 AACR.