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.
Highlights
Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 15%–30% of breast cancers and results in high levels of HER2 protein expression [1]
In this study we show for the first time that elevated Bcl-2-associated athanogene 1 (BAG-1) protein expression correlates with that of HER2, is important for optimal growth of some HER2-overexpressing breast cancer cells, and impedes the growth-inhibitory effect of trastuzumab
Analysis of the METABRIC patient cohort [32] revealed that BAG-1 mRNA is increased in HER2+/ ER+ as well as HER2+/ER- breast tumors compared to normal breast epithelium, and in HER2+ cell lines BAG-1 protein expression is elevated
Summary
Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in 15%–30% of breast cancers and results in high levels of HER2 protein expression [1]. This is accompanied by increased HER2 signaling and promotes malignant cell growth and survival [2]. In the neoadjuvant setting treatment with trastuzumab plus lapatinib (Neo-ALTTO) [8] and trastuzumab plus pertuzumab (Neosphere) [9] results in improved pathological complete response These data suggest that combination targeted therapies have great potential
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