Heme Oxygenase Modulates AC2M2 Mouse Breast Cancer Growth and Progression

Abstract

Heme oxygenase (HO) is the enzyme that breaks down heme to form carbon monoxide, free iron, and biliverdin. The two major isoforms, HO-1 (inducible) and HO-2 (constitutive), are involved in a number of physiological functions, including apoptosis, inflammation, and angiogenesis. In cancerous cells these effects may promote growth, tumour cell survival, and metastasis. Many tumour types have demonstrated increased levels of HO, and research has shown that HO inhibition results in decreased tumour growth. Previous work using metalloporphyrin-based compounds identified HO inhibition as a potential therapy for some cancers, but these compounds are limited by their lack of selectivity. Novel azole-based HO inhibitors (QC-xx) have demonstrated increased in vitro selectivity for HO and were tested for their effects on AC2M2 mouse breast cancer growth and progression. QC-xx demonstrated a concentration-dependent decrease in AC2M2 cell viability and a decrease in endothelial cell tube-like sprouting in an in vitro model of angiogenesis. While there was some evidence that QC-xx treatment could delay primary AC2M2 tumour growth and the development of lung metastases in vivo, the results were inconclusive. The effects of QC-xx on HO activity were different between rats, from which the initial HO data was obtained, and mice, from which our AC2M2 cells were derived. Further examination indicates that HO activation may help elucidate the role of HO in AC2M2 mouse breast cancer growth and progression. The findings will help determine whether HO is an appropriate target in the treatment of breast cancer.