Mutations in the gene BRCA1 are associated with about 5% of breast cancers. In the remainder of breast cancers there are still decreased levels of BRCA1 present. Due to this it is believed that the normal role of BRCA1 is to suppress tumors.
High levels of VEGF (Vascular Endothelial Growth Factor) in breast cancer patients is an indicator of the aggressiveness of the disease. This is because VEGF leads to angiogenesis. Angiogenesis is the process of growing new blood vessels. When tumors grow to a certain size the cells within it can’t get enough oxygen – a condition called: hypoxia. Hypoxia could otherwise cause a cell to die, but cancer cells find a way around this. They start releasing VEGF, resulting in new blood vessels coming to the tumor thus providing the needed oxygen and other nutrients.
Now bear with me – it gets a bit more complicated – for a cell to make more VEGF, it first needs more of the transcription factor called HIF-1 (Hypoxia Inducible Factor). When a cell is in a condition of no oxygen (hypoxia), HIF-1 is stabilized and plenty of it is available.
So this is what we have so far:
A cell is in a state of hypoxia (e.g. within a tumor), this results in an increase in HIF-1, which results in more VEGF, which results in an increase in angiogenesis – providing the cancerous cells the oxygen they need to stay alive.
Hypoxia —–> HIF-1 —–> VEGF —–> angiogenesis
So what does BRCA1 have to do with this? Recent research by Insoo Bae of Georgetown University now shows that BRCA1 helps to stabilize HIF-1. On one hand this data helps to explain why some earlier research found lower levels of VEGF in women with BRCA1 mutations. If the BRCA1 gene is mutated, its corresponding protein is likely to either not be present or to not function properly. If the BRCA1 protein is not present to help stabilize HIF-1, then less VEGF will be made.
However, it contradicts other data in which suggests that BRCA1 is a tumor suppressor since it shows that decreased levels of BRCA1 should result in less VEGF and therefore, less angiogenesis.
So what is the answer to this paradox? No one knows yet, but Insoo Bae’s group suggests that the decrease in BRCA1 in breast cancers may not be responsible for increase in angiogenesis in these cancers.
Stay tuned to this blog for more information about the role of BRCA1 in breast cancer in the coming weeks, months or however long it takes!
Insoo Bae’s paper about this research was published in the May 12, 2006 volume 281, Number 19 issue of the Journal of Biological Chemistry.
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