| Summary: | Regions of insufficient oxygen, hypoxia, occur in most solid tumours, including breast cancer. Hypoxia occurs due to malformed tumour vasculature and uncontrolled cell proliferation and is associated with therapy resistance and an overall poor patient prognosis. Of all the breast cancer subtypes, hypoxia is particularly evident in triple negative breast cancer (TNBC). A wealth of evidence suggests that cyclic hypoxia is commonplace in solid tumours and is associated with the most aggressive disease including increased metastasis. Our laboratory has recently developed a physiologically relevant cyclic protocol that fluctuates between <0.1% O2 and 2% O2. The aim of this project was to characterise the biological response of TNBC to cyclic hypoxia compared to static <0.1% O2 and static 2% O2. We found that cyclic hypoxia induces a differential gene expression profile compared to static <0.1% O2 and static 2% O2, in which there are 87 uniquely expressed genes in cyclic hypoxia. The cell cycle dynamics between the three hypoxic conditions were distinct, with cyclic hypoxia inducing an S-phase accumulation. Cyclic hypoxia exposed TNBC showed decreased radiosensitivity comparative to 2% O2, which we attribute to the S-phase accumulation. Despite a decrease in radiosensitivity of TNBC exposed to cyclic hypoxia, cyclic hypoxia appears a challenging environment for TNBC cell lines and results in decreased cell viability compared to <0.1% O2 and 2% O2. Together, our data shows that the biological response to hypoxia is dependent on the exact nature of the hypoxic conditions to which the cells are exposed, and that cyclic hypoxia can increase therapy resistance.
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