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Oncotarget. 2016 Apr 5;7(14):18851-64. doi: 10.18632/oncotarget.7944.

A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells.

Author information

1
Cancer Research UK Centre Cancer Sciences Unit, Southampton General Hospital, Southampton, United Kingdom.
2
University Hospital Southampton, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
3
Institute of Pharmacy/Pharmacognosy, Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
4
Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.

Abstract

Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial.

KEYWORDS:

BAG-1; HER2; breast cancer; resistance; trastuzumab

PMID:
26958811
PMCID:
PMC4951334
DOI:
10.18632/oncotarget.7944
[Indexed for MEDLINE]
Free PMC Article

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