A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells
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Emmanouil Papadakis1, Natalia Robson1, Alison Yeomans1, Sarah Bailey1, Stephanie Laversin1, Stephen Beers1, A. Emre Sayan1, Margaret Ashton-Key1,2, Stefan Schwaiger3, Hermann Stuppner3, Jakob Troppmair4, Graham Packham1, Ramsey Cutress1,2
1Cancer Research UK Centre Cancer Sciences Unit, Southampton General Hospital, Southampton, United Kingdom
2University Hospital Southampton, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom
3Institute of Pharmacy/Pharmacognosy, Center of Molecular Biosciences, University of Innsbruck, Innsbruck, Austria
4Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
Emmanouil Papadakis, e-mail: firstname.lastname@example.org
Ramsey Cutress, e-mail: email@example.com
Keywords: breast cancer, BAG-1, HER2, trastuzumab, resistance
Received: December 11, 2015 Accepted: February 13, 2016 Published: March 06, 2016
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.
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