Abstract
Triple-negative breast cancer (TNBC) represents a relatively small proportion of all BCs but a relatively large proportion of BC-related death. Thus, more effective therapeutic strategies are needed for the management of TNBC. We demonstrated that the stimulation of apoptosis by the binding of secreted acetylated-apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1) to the receptor for advanced glycation end products (RAGE) was essential for TNBC cell death in response to hyperacetylation. The aim of the present study was to assess the potential therapeutic efficacy of secretory Ac-APE1/Ref-1 in orthotopic TNBC xenografts in vivo. We found that hyperacetylation in xenografts caused secretion of Ac-APE1/Ref-1 into the blood, where the factor bound directly to RAGE in hyperacetylated tumor tissues. Hyperacetylation in the TNBC xenografts induced strong inhibition of tumor growth and development, leading to apoptotic cell death, accompanied by increased RAGE expression and generation of reactive oxygen species. Tissues exhibited markedly higher counts of apoptotic bodies, a reduced proliferation index, and reduced neovascularization compared with control tumors. Ac-APE1/Ref-1-stimulated apoptosis was markedly reduced in RAGE-knockdown tumors compared with RAGE-overexpressing tumors, even in the presence of hyperacetylation. The function of secreted Ac-APE1/Ref-1 was confirmed in other hyperacetylated TNBCs xenografts using BT-549 and MDA-MB-468 cells, demonstrating its relevance as an anti-cancer molecule.
Highlights
Breast cancer is the most common cancer in women worldwide[1]
We previously suggested that hyperacetylation of Triple-negative breast cancer (TNBC) cells resulted in cell death through the action of secreted Ac-APE1/Ref-1, which functioned as an apoptotic trigger[12]
Any appreciable effects of rh Ac-APE1/Ref-1 on cell viability and DNA fragmentation were not observed in normal cells including human mammary epithelial cells (HMECs), and umblical vein endothelial cells (HUVECs), even in hyperacetylated conditions. These results clearly demonstrate that Ac-APE1/Ref-1 possesses potent chemotherapeutic efficacy against hyperacetylated TNBCs but not normal cells based on stimulation of cell death by receptor for advanced glycation end products (RAGE)-dependent triggering of Ac-APE1/Ref-1
Summary
Breast cancer is the most common cancer in women worldwide[1]. Triple-negative breast cancer (TNBC) comprises approximately 15% of all breast cancers and exhibits a higher histological grade, higher metastatic occurrence, and earlier recurrence than other breast cancer types, resulting in poor prognoses[2,3,4]. We showed that stimulation by secretory acetylated-apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1) binding to up-regulated receptor for advanced glycation end products (RAGE) was essential for tumor cell death[12]. Binding of RAGE to S100A8/A9 enhances the activity of natural killer cells and suppresses tumor growth in vivo[22] These findings are consistent with extracellular Ac-APE1/Ref-1 promoting cell death through RAGE in response to hyperacetylation, leading to inhibition of cancer cell proliferation and induction of apoptosis, and not via downregulation of APE1/Ref-1. Because hyperacetylation induced increased RAGE expression and apoptosis mediated by autocrine and/ or paracrine mechanisms involving secreted Ac-APE1/Ref-1 in TNBC cells[12], we hypothesized that secreted Ac-APE1/Ref-1 could promote apoptosis in hyperacetylated TNBC xenografts in vivo. We tested this hypothesis in xenograft models using three human basal subtyped TNBC cell lines (MDA-MB-231, BT-549, and MDA-MB-468)
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