Researchers explored the development of tumours in carriers of BRCA mutations, to improve prevention and early detection of breast and ovarian cancer.

Health

Cancer is overtaking heart disease as the main cause of death in Europe, largely due to the lack of cancer preventive measures. Although new treatments for breast cancer mean that most women survive the disease, for those with some types, such as triple negative breast cancer, the prognoses remain poor. “Women with a germline mutation in BRCA genes have an excessively high risk of developing breast cancer, and the majority of these cancers are triple negative breast cancers,” explains Martin Widschwendter, professor in Women’s Cancer at University College London and BRCA-ERC project coordinator. “Their risk of ovarian cancer is also very high,” he adds. In the BRCA-ERC project, which was funded by the European Research Council (ERC), Widschwendter led a team aiming to uncover new insights into the contributors of heightened cancer risk in BRCA mutation carriers, to advance preventive measures. “Our most important results include new information on the role of progesterone in breast cancer development, new markers that indicate increased breast cancer risk in breast tissue, and new surrogate markers in easy-to-access tissue that could be implemented in clinical practice,” explains Widschwendter.

Studying hormone levels in the context of BRCA mutations

Through the BRCA-ERC project, the team studied daily oestrogen and progesterone levels in saliva and urine samples from a cohort of women with and without BRCA mutations – the first time that such a detailed study of hormones across an entire menstrual cycle had been done. ”We found that progesterone levels were higher throughout the menstrual cycle in women with a BRCA1 mutation compared to controls, particularly during the luteal (post-ovulation) phase,” notes Widschwendter. “We hypothesised that blocking progesterone signalling in women at high risk of breast cancer could prevent the disease.”

Potential cancer prevention and early detection

In collaboration with researchers from the Karolinska Institute, the BRCA-ERC team found that mifepristone, a drug that blocks progesterone, could lead to a slower turnover in luminal progenitor cells – those progenitor cells that eventually lead to cells lining the lumen of breast ducts. “This indicates a potential reduction in cancer risk,” says Widschwendter. “These new data support the use of mifepristone for breast cancer prevention.” The researchers also developed a new DNA methylation marker in breast tissue known as WID-Breast29, which identifies the proportion of luminal progenitor cells that have undergone a high number of divisions. WID-Breast29 was much higher in breast cancer tissue compared to normal tissue, supporting its use as a biomarker. The BRCA-ERC team also investigated new markers for early detection of ovarian cancer using cell-free DNA methylation, inherited modifications of DNA. In a diagnostic setting, the specificity was 97.6 %. “We continue to work on novel early cancer detection markers for endometrial and cervical cancers too,” adds Widschwendter.

A collaborative effort to prevent cancer

BRCA-ERC involved a team of clinicians, nurses, basic scientists, systems biologists, bioinformaticians and clinical trialists who worked closely together to deliver the research. “While our ultimate aim is to prevent cancers from occurring, early detection of cancer remains an important target, and we have also generated new data on tests for ovarian, endometrial and cervical cancers during this project,” says Widschwendter. The team received an ERC Proof of Concept award to continue the research under the BRCA-PREVENT project.

Keywords

BRCA-ERC, genes, cancer, mutation, prevent, early, detection, tumours, breast cancer, biomarker