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, Ma Ángeles Castilla, Antonio González-Martin, Sonia Pernas, Amparo Cano, Javier Cortes, Paolo G. Nuciforo, Vicente Peg, José Palacios, Miguel Ángel Pujana, Joaquín ArribasGema Moreno-Bueno

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)56295-56308
JournalOncotarget
Volume7
Issue number35
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • Clinical behaviour
  • Gasdermin B
  • HER2-positive breast cancer
  • Predictive biomarker
  • Resistance to therapy

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