Role of the expression of collagen prolyl-4-hydroxylase α subunits 1 and 2 in the development and prognosis of breast cancer
Background: The expression of prolyl-4-hydroxylase (P4H), an enzyme involved in collagen biosynthesis, is significantly upregulated during breast cancer development and progression. However, the molecular mechanisms by which P4H expression in cancer cells induces progression have not been elucidated. Thus, we aimed to determine the significance of the expression of isoforms 1 and 2 of P4H in breast cancer. Methods: We performed immunohistochemical analysis for P4HA1 and P4HA2 on the tumor samples obtained from 182 patients with breast cancer and examined the correlation between clinicopathological factors and markers related to epithelial-mesenchymal transition and ischemia. Protein expression levels were investigated using western blotting. In addition, breast cancer cell cultures were used to characterize the expression. Results: Expression of both P4HA1 and P4HA2 was upregulated in cancer cells compared with that in normal mammary glands; the high-P4H expression group tended to have a poorer prognosis than the low-P4H expression group. In particular, P4HA2 was strongly associated with tumor grade; P4HA2 expression showed a weak negative correlation with HIF-2α expression. In cultured breast cancer cells, the immunohistological expression of P4H and HIF increased to various degrees under hypoxia, while P4H protein levels increased in a time-dependent manner. Conclusion: P4HA2 can be used as a marker of breast cancer grade and a prognostic factor. Differential expression of P4HA1 and P4HA2 was observed in an ischemic environment, suggesting that each may be affected by the type of collagen involved.