Artículo
Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC
Güttlein, Leandro
; Benedetti, Lorena Gabriela
; Fresno Rodríguez, Cristóbal
; Spallanzani, Raúl Germán
; Mansilla, Sabrina Florencia
; Rotondaro, Cecilia
; Raffo Iraolagoitia, Ximena Lucía
; Salvatierra, Edgardo; Bravo, Alicia I.; Fernandez, Elmer Andres
; Gottifredi, Vanesa
; Zwirner, Norberto Walter
; Llera, Andrea Sabina
; Podhajcer, Osvaldo Luis
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Fecha de publicación:
03/2017
Editorial:
American Association for Cancer Research
Revista:
Molecular Cancer Research
ISSN:
1541-7786
e-ISSN:
1557-3125
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Cáncer
,
Sparc
,
Her2-Enriquecido
,
Metástasis
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Identificadores
Colecciones
Articulos(IIBBA)
Articulos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Articulos de INST.DE INVEST.BIOQUIMICAS DE BS.AS(I)
Citación
Güttlein, Leandro; Benedetti, Lorena Gabriela; Fresno Rodríguez, Cristóbal; Spallanzani, Raúl Germán; Mansilla, Sabrina Florencia; et al.; Predictive Outcomes for HER2-enriched Cancer Using Growth and Metastasis Signatures Driven By SPARC; American Association for Cancer Research; Molecular Cancer Research; 15; 3; 3-2017; 304-316
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