title: Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC.
abstract: 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.
authors.affiliation: Laboratorio de Terapia Molecular y Celular, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Leandro N
authors.initials: LN
authors.lastname: Güttlein
authors.affiliation: Laboratorio de Terapia Molecular y Celular, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Lorena G
authors.initials: LG
authors.lastname: Benedetti
authors.affiliation: Unidad Asociada: Área de Cs. Agrarias, Ingeniería, Cs. Biológicas y de la Salud. CONICET. Universidad Católica de Córdoba, Córdoba, Argentina.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Fresno
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental-CONICET. Buenos Aires, Argentina.
authors.forename: Raúl G
authors.initials: RG
authors.lastname: Spallanzani
authors.affiliation: Laboratorio de Ciclo Celular y Estabilidad Genómica, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Sabrina F
authors.initials: SF
authors.lastname: Mansilla
authors.affiliation: Laboratorio de Terapia Molecular y Celular, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rotondaro
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental-CONICET. Buenos Aires, Argentina.
authors.forename: Ximena L
authors.initials: XL
authors.lastname: Raffo Iraolagoitia
authors.affiliation: Laboratorio de Terapia Molecular y Celular, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Salvatierra
authors.affiliation: Unidad de Inmunopatología, Hospital Interzonal General de Agudos Eva Perón, San Martín, Provincia de Buenos Aires, Argentina.
authors.forename: Alicia I
authors.initials: AI
authors.lastname: Bravo
authors.affiliation: Unidad Asociada: Área de Cs. Agrarias, Ingeniería, Cs. Biológicas y de la Salud. CONICET. Universidad Católica de Córdoba, Córdoba, Argentina.|Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Elmer A
authors.initials: EA
authors.lastname: Fernández
authors.affiliation: Laboratorio de Ciclo Celular y Estabilidad Genómica, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gottifredi
authors.affiliation: Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental-CONICET. Buenos Aires, Argentina.|Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Norberto W
authors.initials: NW
authors.lastname: Zwirner
authors.affiliation: Laboratorio de Terapia Molecular y Celular, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Llera
authors.affiliation: Laboratorio de Terapia Molecular y Celular, IIBBA, Fundación Instituto Leloir, CONICET, Buenos Aires, Argentina. opodhajcer@leloir.org.ar.
authors.forename: Osvaldo L
authors.initials: OL
authors.lastname: Podhajcer
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015676:Osteonectin; D018719:Erb-b2 Receptor Tyrosine Kinases; C577241:SPARC protein, human; C578250:SPARC protein, mouse; C524056:Erbb2 protein, mouse