Oncotarget

Research Papers:

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

Marta Hergueta-Redondo _, David Sarrio, Ángela Molina-Crespo, Rocío Vicario, Cristina Bernadó-Morales, Lidia Martínez, Alejandro Rojo-Sebastián, Jordi Serra-Musach, Alba Mota, Ángel Martínez-Ramírez, Maria Ángeles Castilla, Antonio González-Martin, Sonia Pernas, Amparo Cano, Javier Cortes, Paolo G. Nuciforo, Vicente Peg, José Palacios, Miguel Ángel Pujana, Joaquín Arribas, Gema Moreno-Bueno

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Abstract

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

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.

Author Information

Marta Hergueta-Redondo
Primary Contact  _

David Sarrio

Ángela Molina-Crespo

Rocío Vicario

Cristina Bernadó-Morales

Lidia Martínez

Alejandro Rojo-Sebastián

Jordi Serra-Musach

Alba Mota

Ángel Martínez-Ramírez

Maria Ángeles Castilla

Antonio González-Martin

Sonia Pernas

Amparo Cano

Javier Cortes

Paolo G. Nuciforo

Vicente Peg

José Palacios

Miguel Ángel Pujana

Joaquín Arribas

Gema Moreno-Bueno


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