Hypoxia is associated with increased expression of APOBEC genes in breast cancer

Abstract

Background: APOBEC expression or its hyperactivity is common in breast cancers and plays an essential role in promoting tumour progression and conferring intra-tumoural heterogeneity. Hypoxia or low oxygen is an element that shapes the tumour microenvironment, contributing to its malignancy. There have been hints at hypoxia influencing APOBEC3B activity, but the association in breast cancers is underexplored. Aim and Objectives: This study aims to establish a direct link between hypoxia and APOBEC expression. Materials and Methods: Three breast cancer datasets present on cbioportal were used. The datasets were first individually sorted based on their collective expression of hypoxic genes (Buffa signature) and patients were classified as having low hypoxia (LH) or high hypoxia (HH). The mRNA expression of APOBEC3A and APOBEC3B was compared between the two groups, as was the survival probability. The expression of APOBEC genes was also evaluated using the real-time quantitative polymerase chain reaction in three breast cancer cell lines exposed to normoxic (20% oxygen) or hypoxic conditions, defined as acute (1% oxygen) or chronic (0.1% oxygen). Results: Patients in the HH group displayed significantly higher expression of APOBEC3A and APOBEC3B, as well as worse survival, than patients in the LH group. Expression analysis of APOBECs in breast cancer cell lines showed no significant changes. Conclusion: An association exists between the presence of hypoxia in breast tumours and the expression of APOBEC3A and APOBEC3B. While this could not be shown in vitro, further studies with different breast cancer cell types and varied hypoxic conditions might be necessary to validate the patient findings.