Guttlein, L.N.; Benedetti, L.G.; Fresno, C.; Spallanzani, R.G.; Mansilla, S.F.; Rotondaro, C.; Iraolagoitia, X.L.R.; Salvatierra, E.; Bravo, A.I.; Fernandez, E.A.; Gottifredi, V.; Zwirner, N.W.; Llera, A.S.; Podhajcer, O.L."Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC" (2017) Molecular Cancer Research. 15(3):304-316
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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. © 2017 American Association for Cancer Research.


Documento: Artículo
Título:Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC
Autor:Guttlein, L.N.; Benedetti, L.G.; Fresno, C.; Spallanzani, R.G.; Mansilla, S.F.; Rotondaro, C.; Iraolagoitia, X.L.R.; Salvatierra, E.; Bravo, A.I.; Fernandez, E.A.; Gottifredi, V.; Zwirner, N.W.; Llera, A.S.; Podhajcer, O.L.
Filiación:Laboratorio de Terapia Molecular y Celular, IIBBA, Fundacion Instituto Leloir, CONICET, Av. Patricias Argentinas 435, Buenos Aires, C1405BWE, Argentina
Unidad Asociada: Area de Cs. Agrarias Ingeniería, Cs. Biologicas y de la Salud. CONICET, Universidad Catolica de Cordoba, Cordoba, Argentina
Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina
Laboratorio de Ciclo Celular y Estabilidad Genomica, IIBBA, Fundacion Instituto Leloir, CONICET, Buenos Aires, Argentina
Unidad de Inmunopatología, Hospital Interzonal General de Agudos Eva Peron, Provincia de Buenos Aires, Argentina
Facultad de Ciencias Exactasy Naturales, Departamento de Química Biologica, Universidad de Buenos Aires, Buenos Aires, Argentina
Facultad de Ciencias Exactas Físicas y Naturales, Universidad Nacional de Cordoba, Cordoba, Argentina
Palabras clave:cyclooxygenase 2; epidermal growth factor receptor 2; osteonectin; short hairpin RNA; epidermal growth factor receptor 2; Erbb2 protein, mouse; osteonectin; SPARC protein, human; SPARC protein, mouse; animal cell; animal experiment; animal model; Article; breast cancer; cell expansion; clinical outcome; control; controlled study; female; gene expression; human; human tissue; major clinical study; metastasis; mouse; myeloid-derived suppressor cell; nonhuman; predictive value; primary tumor; priority journal; tumor growth; animal; Bagg albino mouse; breast tumor; cell growth; enzymology; experimental mammary neoplasm; genetics; MCF-7 cell line; metabolism; metastasis; pathology; physiology; prognosis; treatment outcome; tumor cell line; Animals; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Female; Humans; Mammary Neoplasms, Experimental; MCF-7 Cells; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Osteonectin; Prognosis; Receptor, ErbB-2; Treatment Outcome
Página de inicio:304
Página de fin:316
Título revista:Molecular Cancer Research
Título revista abreviado:Mol. Cancer Res.
CAS:epidermal growth factor receptor 2, 137632-09-8; osteonectin, 104052-78-0; Erbb2 protein, mouse; Osteonectin; Receptor, ErbB-2; SPARC protein, human; SPARC protein, mouse


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---------- APA ----------
Guttlein, L.N., Benedetti, L.G., Fresno, C., Spallanzani, R.G., Mansilla, S.F., Rotondaro, C., Iraolagoitia, X.L.R.,..., Podhajcer, O.L. (2017) . Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC. Molecular Cancer Research, 15(3), 304-316.
---------- CHICAGO ----------
Guttlein, L.N., Benedetti, L.G., Fresno, C., Spallanzani, R.G., Mansilla, S.F., Rotondaro, C., et al. "Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC" . Molecular Cancer Research 15, no. 3 (2017) : 304-316.
---------- MLA ----------
Guttlein, L.N., Benedetti, L.G., Fresno, C., Spallanzani, R.G., Mansilla, S.F., Rotondaro, C., et al. "Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC" . Molecular Cancer Research, vol. 15, no. 3, 2017, pp. 304-316.
---------- VANCOUVER ----------
Guttlein, L.N., Benedetti, L.G., Fresno, C., Spallanzani, R.G., Mansilla, S.F., Rotondaro, C., et al. Predictive outcomes for HER2-enriched cancer using growth and metastasis signatures driven by SPARC. Mol. Cancer Res. 2017;15(3):304-316.