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BRCA1 cancer study suggests alternative to major surgery

31 March 2014

By Dr Sarah Spain

Appeared in BioNews 748

BRCA1 mutations put carriers at high risk of cancer by failing to protect cells against the effects of high levels of oestrogen hormone found in breast and ovary tissue, researchers have established.

A link between oestrogen and BRCA1 had long been suspected, but the study confirms it and demonstrates the underlying mechanism.

The information could allow the development of preventative treatment strategies using already available drugs as an alternative to the major surgery many women choose to have to reduce their cancer risk.

One in 1,000 women in the UK have BRCA1 mutations that carry with them up to an 85 percent increased risk of breast cancer and up to a 45 percent increased risk of ovarian cancer. BRCA1 mutations are mostly inherited.

Currently, the only way to reduce the increased cancer risk from a BRCA1 mutation is major surgery in the form of double mastectomy (removal of both breasts) and oophorectomy (removal of ovaries).

BRCA1 is a tumour suppressor gene and normally works to maintain genome stability. As BRCA1 performs this function in all cells, the researchers were interested in why mutations mainly led to tumour formation in tissues regulated by oestrogen.

In cell culture experiments, the researchers showed a clear link between high levels of hormones and DNA damage, which can cause cancer. They reported that oestrogen and its metabolites can cause double-strand breaks in DNA in certain breast cells.

They also showed that BRCA1 is required to repair these DNA breaks and also to regulate the expression of oestrogen-metabolising enzymes in breast tissue, thus preventing DNA damage from oestrogen metabolites.

Finally, the scientists looked at human cell lines carrying BRCA1 mutations. They concluded that BRCA1-mutated cells in oestrogen-regulated tissue, such as the breast and ovary, cannot counteract high levels of hormones and their metabolites, and this leads to DNA damage and tumour formation.

'It's the first really credible evidence that oestrogen is driving cancer in women with a BRCA1 gene mutation', said study leader Dr Kienan Savage from Queen's University Belfast. 'Because of this discovery, we now have the opportunity to propose an alternative treatment to surgery. It also opens up the possibility of pausing treatment for a period for women to have children, if desired'.

Drugs already exist that can reduce oestrogen levels. The researchers now hope to secure funding to test them as possible preventative treatments in clinical trials later in the year.

The research, which took four years to complete, was funded by Cancer Focus Northern Ireland and Cancer Research UK. Cancer Focus Northern Ireland chief executive Roisin Foster said the research 'has the potential in the foreseeable future to benefit women all over the world'.

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