Antitumor role of heme oxygenase-1 in breast cancer

Abstract

It has been reported that HO-1 can translocate to multiple subcellular compartments and can have non-enzymatic signaling roles. Thus, in the nucleus the protein acts as a transcriptional co-regulator protein and can bind and modulate other important proteins. HO-1 is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, being this also true for breast cancer (BC). In this work we intended to address this discrepancy regarding the role of HO-1 in BC. HO-1 was detected in human BC tissues, and its protein levels correlated with reduced tumor size (p=0.046) and longer overall survival time of patients (p=0.004). Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade (p=0.05). However, nuclear HO-1 was not significantly associated to patient overall survival time (p = 0.13). In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduced the tumor burden in two different animal models of BC. Furthermore, the activation of HO-1 in several BC cell lines reduce the cellular viability by inducing apoptosis (p<0.05) and cell cycle arrest (p<0.003) and decrease the cellular migration, invasion and adhesion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination (p=0.020). In concordance, HO-1 was associated with reduced number of lymph node metastases (p=0.0243) and higher levels of E-cadherin (p=0.0026) in human BC. In addition, the enzymatic activity of HO-1 in nuclear and cytoplasmic fraction was studied. In conclusion, we demonstrated that HO-1 displays antitumor activities in BC. Furthermore, our studies suggest that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types.