Gasdermin B expression predicts poor clinical outcome in HER2-positive breast cancer.

// Marta Hergueta-Redondo 1 , David Sarrio 1 , Angela Molina-Crespo 1 , Rocio Vicario 2 , Cristina Bernado-Morales 2 , Lidia Martinez 1 , Alejandro Rojo-Sebastian 3 , Jordi Serra-Musach 4 , Alba Mota 1, 5 , Angel Martinez-Ramirez 6 , Maria Angeles Castilla 7 , Antonio Gonzalez-Martin 8 , Sonia Pernas 4 , Amparo Cano 1 , Javier Cortes 9, 10 , Paolo G. Nuciforo 11 , Vicente Peg 12 , Jose Palacios 7, 13 , Miguel Angel Pujana 4 , Joaquin Arribas 2, 9, 11 , Gema Moreno-Bueno 1, 5 1 Biochemistry Department, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomedicas “Alberto Sols” (CSIC-UAM), IdiPAZ, Madrid, Spain 2 Preclinical Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain 3 Pathology Department, MD Anderson Cancer Center, Madrid, Spain 4 Breast Cancer and Systems Biology Unit, ProCURE, Catalan Institute of Oncology, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain 5 Translational Research Laboratory, MD Anderson Internacional Foundation, Madrid, Spain 6 Cytogenetics Department, MD Anderson Cancer Center, Madrid, Spain 7 Pathology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain 8 Oncology Department, MD Anderson Cancer Center, Madrid, Spain 9 Clinical Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain 10 Oncology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain 11 Molecular Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain 12 Pathology Department, Hospital Vall d’Hebron University, Barcelona, Spain 13 Pathology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain Correspondence to: Gema Moreno-Bueno, email: gmoreno@iib.uam.es Marta Hergueta-Redondo, email: mhergueta@cnio.es 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 ABSTRACT 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.