Hypoxia and tumour angiogenesis involved in breast cancer progression and targets for therapy

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Tumours cannot grow above 1-2 mm in diameter without developing a new blood supply. We, and others, have shown that the number of blood vessels in breast cancer is related to prognosis, and that multiple growth-factor pathways control angiogenesis. One of the most important ones is vascular endothelial growth factor and thymidine phosphorylase. Both are targets of therapy, and currently there are trials running inhibiting VEGF signalling pathway and also using prodrugs activated by thymidine phosphorylase to produce cytotoxic agents. Hypoxia is a major factor switching on angiogenesis, and new approaches using the hypoxia signalling pathways to activate gene therapy in breast cancer have been initiated. Hypoxia activates vascular endothelial growth factor production by the transcription factor hypoxia inducible factor 1a (hif1), which binds to specific DNA sequences. Using DNA constructs with multimers of these response elements has generated reagents that will specifically switch on under hypoxia and activate prodrugs. Since tumours are much more hypoxic than normal tissues, this should provide marked differential expression. Also, these areas of tumours are resistant to radiotherapy, so it will be particularly useful in worse prognosis resistant tumours. We raised antibodies to hif1, and to another member of the family, hif2.

Staining breast tumours showed marked induction of hif2 expression in stromal macrophages, whereas hif1 was expressed in the epithelium around the areas of necrosis. Thus, there are two different hypoxia-regulated pathways activated. We have also screened for novel genes induced by hypoxia, and found that another transcription-factor pathway downstream of hif as well as enzymes regulating pH are modified. These are new potential targets for therapy.