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Breakthrough Breast Cancer scientists have found the first direct link between breast cancer risk and genetically determined levels of the hormone oestrogen in younger women, according to a paper published online in the Journal of the National Cancer Institute.
The important study, which used data from the Breakthrough Generations Study, found an alteration in a gene that is involved in the breakdown of oestrogen and is also associated with a modest reduction in breast cancer risk in pre-menopausal women.
Study author Dr Olivia Fletcher, from the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR), said: “This is the first time anyone has found a DNA change that is directly associated both with hormone levels and breast cancer risk in younger women. Scientists have suspected this link exists, but no one has been able to prove it until now. This represents an important step forward in our understanding of the link between hormones and breast cancer. Ultimately, it may have implications for the way we monitor and treat breast cancer.”
Although this DNA change is only one part of a very complex picture of the relationship between hormones and breast cancer, variants such as this could potentially form part of a genetic test that could help predict young women’s risk of breast cancer.
Sex hormones such as oestrogen are known to be important in breast cancer development. Previous studies have found that post-menopausal women with higher levels of particular hormones are at greater risk of breast cancer, however the direct evidence in pre-menopausal women has so far been inconsistent.
The scientists set out to find genetic variants involved in the synthesis or breakdown of sex hormones. They first measured markers of hormone levels in the urine and blood of more than 700 healthy pre-menopausal women, using a process that was specially designed to account for variation in levels during the menstrual cycle. They then examined the women’s DNA, focusing on 42 genes that are known to be involved in the synthesis or breakdown of sex hormones.
When they compared women’s hormone levels with each of the variants that they tested, they identified one genetic variant that was more common in women who had lower urinary levels of a particular oestrogen breakdown product called oestrone glucuronide. The variant was a single letter change in the DNA at position 7q22.1, not far from the CYP3A gene cluster. It was associated with a 22 per cent reduction in urinary oestrone glucuronide levels.
The team then tested this variant in a further 10,551 breast cancer patients and 17,535 healthy controls, and found the DNA change was more common in healthy women. The variant was associated with a modest – nine per cent – reduction in breast cancer risk in women diagnosed at or before age 50, but not in older women.
One of the family of CYP3A genes, CYP3A4 is responsible for breaking down around half of all clinically used drugs, including some of those used in the treatment of breast cancer, so the team believe their finding may also have wider implications. It is possible that the gene variant may influence the way women respond to drugs.
Dr Fletcher added: “As we move towards a future of personalised medicine, we hope to test people’s genes to not only decide which drugs to give them, but also to tailor the most effective doses for the individual. This research has revealed that this set of genes warrants further investigation for the effect they may have on the way the body processes drugs.”
Dr Julia Wilson, Head of Research at Breakthrough Breast Cancer, said: “This research is a crucial first step to understanding breast cancer in younger women and how we can more effectively treat it. The gene identified raises the prospect of doctors knowing not only what treatment a breast cancer patient needs, but also what dose, so more women can survive the disease. This work used data from the Breakthrough Generations Study, which aims to unravel the causes of breast cancer so we can treat it more effectively and prevent it in the future.”
Dr Olivia Fletcher's work, as part of the Garfield Weston Genetic Epidemiology Project, which runs alongside the Breakthrough Generations Study, is funded this year by the Garfield Weston Foundation.