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

Marta Hergueta-Redondo1, David Sarrio1, Ángela Molina-Crespo1

  • 1Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.

Oncotarget
|July 28, 2016
PubMed

Insights

Gasdermin B (GSDMB) is a gene co-amplified with ERBB2 in HER2-positive breast cancer. GSDMB overexpression correlates with poor prognosis and trastuzumab resistance, identifying it as a potential therapeutic target.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Approximately 30-40% of HER2-positive breast cancers exhibit resistance to targeted therapies, with underlying mechanisms often unclear.
  • The ERBB2 gene is frequently co-amplified with neighboring genes, suggesting their potential involvement in HER2-positive breast cancer progression and treatment response.

Purpose of the Study:

  • To investigate the role of Gasdermin B (GSDMB), a gene located near ERBB2, in HER2-positive breast cancer prognosis and response to targeted therapy.
  • To identify potential mechanisms of trastuzumab resistance in HER2-positive breast cancer.

Main Methods:

  • In silico analysis of gene expression and clinical data from 2,096 breast tumors.
  • Validation using three independent cohorts comprising 286 HER2-positive tumors.
  • Assessment of GSDMB gene amplification and protein overexpression.
  • In vitro studies using HER2-positive breast carcinoma cell lines.
  • In vivo studies using Patient Derived Xenografts (PDXs).

Main Results:

  • A significant correlation was found between GSDMB expression and poor prognostic pathological and clinical parameters in HER2-positive breast cancer.
  • GSDMB gene amplification and protein overexpression were observed in approximately 65% of HER2-positive cases across independent cohorts.
  • GSDMB expression was associated with reduced relapse-free survival, lower pathologic complete response rates, positive lymph node status, and increased risk of distant metastasis.
  • GSDMB overexpression promoted survival in trastuzumab-treated HER2-positive breast cancer cells and conferred a trastuzumab resistance phenotype in vivo.

Conclusions:

  • The ERBB2 co-amplified and co-expressed gene GSDMB is a critical determinant of poor prognosis in HER2-positive breast cancer.
  • GSDMB is implicated in resistance to trastuzumab therapy, highlighting its potential as a biomarker and therapeutic target for improving treatment outcomes.
Keywords:
HER2-positive breast cancerclinical behaviourgasdermin Bpredictive biomarkerresistance to therapy

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