Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer

Abstract

Reactive oxygen species (ROS) damage DNA, but the role of ROS in breast carcinoma may not be limited to the mutagenic activity that drives carcinoma initiation and progression. Carcinoma cells in vitro and in vivo are frequently under persistent oxidative stress. In the present review, we outline potential causes of oxygen radical generation within carcinoma cells and explore the possible impact of oxidative stress on the clinical outcome of breast carcinoma.

Figure 1

Oxygen radicals and oxygen insufficiency (hypoxia) co-operatively promote tumour angiogenesis. Breast carcinomas frequently outgrow their blood supply, leading to oxygen insufficiency (hypoxia) within the tumour. Hypoxia causes necrosis, and DNA is subsequently degraded to its constituent bases. Any thymidine released is catabolized by thymidine phosphorylase, an enzyme that is frequently overexpressed within breast carcinomas. Thymidine phosphorylase activity causes oxygen radical production, as described by Brown et al [6]. Reoxygenation of the tumour after hypoxia will drive additional oxygen radical formation. Breast tumours are also oxidatively stressed by nonhypoxic mechanisms, such as glucose deprivation, metabolic alterations and macrophage infiltration. Hypoxia causes the accumulation of the transcription factor HIF-1, which promotes transcription of the angiogenic factor VEGF. HIF-1 levels may also be increased by oxygen radicals. In addition, oxygen radicals increase production of the angiogenic factors VEGF and IL-8 via HIF-1-independent mechanisms.