London School of Hygiene & Tropical Medicine

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 this week in the Journal of the National Cancer Institute.

The important study led by scientists at the London School of Hygiene & Tropical  Medicine and Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR) 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.

Co-author Professor Isabel Dos Santos Silva, head of the Department of Non-communicable Disease Epidemiology at the London School of Hygiene & Tropical Medicine, said: "Previous studies have shown that levels of the sex hormone oestrogen in women who have gone through the menopause are linked to their risk of getting breast cancer later in life. However, it has been difficult to establish whether such a link exists in younger women, partly because oestrogen levels fluctuate markedly throughout a woman's menstrual cycle and are therefore rather difficult to measure accurately.

“We developed a novel approach to specifically capture the variations in oestrogen levels during the menstrual cycle. Using this new approach the study was able to identify for the first time a genetic variant which is linked to both oestrogen levels and breast cancer risk in women aged under 50. These findings are important because they not only better our understanding of the biology of breast cancer but they may also lead to future improvements in the way young women with the disease are diagnosed and treated."

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 postmenopausal women with higher levels of particular hormones are at greater risk of breast cancer, however the direct evidence in premenopausal 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 premenopausal 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.

Senior author Dr Olivia Fletcher from the ICR’s Breakthrough Breast Cancer Research Centre said: “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.”

The study was a collaboration between scientists at the ICR’s Breakthrough Breast Cancer Research Centre and the Division of Genetics and Epidemiology; The Royal Marsden Hospital NHS Foundation Trust; the London School of Hygiene & Tropical  Medicine; the Wellcome Trust Centre for Human Genetics; the Biomedical Research Centre at Guy’s & St Thomas’ NHS Foundation Trust and King’s College London; and The University of Edinburgh in the UK along with University Hospital Galway in Ireland.

The study was funded by Breakthrough Breast Cancer, Breast Cancer Campaign, Cancer Research UK and the Department of Health.

Impact of CYP3A variation on estrone levels and breast cancer risk has published online in Journal of the National Cancer Institute.

• Listen to Professor Isabel Dos Santos Silva talk about her research: Oestrogen Gene Predicts Breast Cancer Risk In Young Women