Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer
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Marta Hergueta-Redondo1, David Sarrio1, Ángela Molina-Crespo1, Rocío Vicario2, Cristina Bernadó-Morales2, Lidia Martínez1, Alejandro Rojo-Sebastián3, Jordi Serra-Musach4, Alba Mota1,5, Ángel Martínez-Ramírez6, Maria Ángeles Castilla7, Antonio González-Martin8, Sonia Pernas4, Amparo Cano1, Javier Cortes9,10, Paolo G. Nuciforo11, Vicente Peg12, José Palacios7,13, Miguel Ángel Pujana4, Joaquín Arribas2,9,11, Gema Moreno-Bueno1,5
1Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ, Madrid, Spain
2Preclinical Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
3Pathology Department, MD Anderson Cancer Center, Madrid, Spain
4Breast Cancer and Systems Biology Unit, ProCURE, Catalan Institute of Oncology, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain
5Translational Research Laboratory, MD Anderson Internacional Foundation, Madrid, Spain
6Cytogenetics Department, MD Anderson Cancer Center, Madrid, Spain
7Pathology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain
8Oncology Department, MD Anderson Cancer Center, Madrid, Spain
9Clinical Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain
10Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
11Molecular Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
12Pathology Department, Hospital Vall d’Hebron University, Barcelona, Spain
13Pathology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
Gema Moreno-Bueno, email: [email protected]
Marta Hergueta-Redondo, email: [email protected]
Keywords: HER2-positive breast cancer, gasdermin B, clinical behaviour, predictive biomarker, resistance to therapy
Received: December 10, 2015 Accepted: July 06, 2016 Published: July 22, 2016
Around, 30–40% of HER2-positive breast cancers do not show substantial clinical benefit from the targeted therapy and, thus, the mechanisms underlying resistance remain partially unknown. Interestingly, ERBB2 is frequently co-amplified and co-expressed with neighbour genes that may play a relevant role in this cancer subtype. Here, using an in silico analysis of data from 2,096 breast tumours, we reveal a significant correlation between Gasdermin B (GSDMB) gene (located 175 kilo bases distal from ERBB2) expression and the pathological and clinical parameters of poor prognosis in HER2-positive breast cancer. Next, the analysis of three independent cohorts (totalizing 286 tumours) showed that approximately 65% of the HER2-positive cases have GSDMB gene amplification and protein over-expression. Moreover, GSDMB expression was also linked to poor therapeutic responses in terms of lower relapse free survival and pathologic complete response as well as positive lymph node status and the development of distant metastasis under neoadjuvant and adjuvant treatment settings, respectively. Importantly, GSDMB expression promotes survival to trastuzumab in different HER2-positive breast carcinoma cells, and is associated with trastuzumab resistance phenotype in vivo in Patient Derived Xenografts. In summary, our data identifies the ERBB2 co-amplified and co-expressed gene GSDMB as a critical determinant of poor prognosis and therapeutic response in HER2-positive breast cancer.
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