BRCA1/2 gene alterations and breast cancer
Cancers develop due to a complex interplay of inherited “genetic” risk factors, environment, and lifestyle. While genetic factors alone only account for approximately 30% of cancer development – meaning environmental and lifestyle factors are key potential targets that could be used to modify individual cancer risk – some genetic alterations confer a particularly high risk for cancer development. One such example is alterations in the BRCA1 and BRCA2 genes: a recent study estimated that 72% of BRCA1 gene alteration carriers will develop a breast cancer by the age of 80. Of those who do, 70% develop a so-called “triple negative” cancer.
Triple negative breast cancers (TNBCs) often occur in younger women and are devastating as they are more aggressive, harder to treat, and more likely to come back than other forms of breast cancer. In part, the aggressiveness of these cancers is because they lack three factors common to other breast cancers that can normally be used to target and treat the disease, including receptors for the hormones oestrogen and progesterone, and growth factor . Targeted treatments against these factors, for instance anti-hormonal treatments, won’t be effective against
Risk-reducing surgeries and modern prevention
To prevent triple negative breast cancer and breast cancer in general, women at very high risk may choose to undergo preventive surgery by removing both breasts. This is known as risk-reducing mastectomy. Awareness about this option has been raised by celebrities, such as Angelina Jolie, who had a risk-reducing mastectomy due to a BRCA1 gene alteration. However, a mastectomy is major surgery that comes with risks, side effects and is often not an easy step to take. New ways to prevent aggressive breast cancers by targeting tumour development and individual risk monitoring could improve the quality of life of women with BRCA gene alterations or otherwise increased risk, and reduce unnecessary surgeries.
Stopping triple negative breast cancer in its tracks
To stop cancer from developing, it’s essential to understand the series of molecular events contributing to it. While triple negative breast cancers themselves become unresponsive to hormones such as progesterone, progesterone plays an important role during cancer development. Progesterone can indirectly, via growth factors, act on the cells known to be the origin of the cancer – so called luminal progenitor cells – causing the cells to divide more often and therefore to ‘age’ more rapidly. This is associated with a higher risk of triple negative breast cancer. Measuring the proportion of “aged” cells in breast tissue could therefore be a step towards identifying individual cancer risk.
Measuring aged cells in the breast
The epigenome – for now we focus on a certain type of the epigenome called “DNA methylation”– is an extra layer of information on our DNA. Our DNA contains all of the genes we inherit from both our parents, and every cell in the body contains all of this DNA. It is DNA methylation that tells the cell which bits of DNA to read, by leaving little marks on top of some of the DNA – so it knows which cell it is and what it is supposed to do. Our lifestyle and environment (such as smoking, pollution, diet etc) can alter these marks and change how the cell behaves. Our recent findings suggest that we can read these marks to hopefully predict the risk someone has of developing cancer in the future.
To find out the number of aged cells in a breast tissue sample, first author Tom Barlett in the research group led by Prof. Widschwendter (Universtät Innsbruck, UCL, Karolinska Institutet) developed a specific new test called “WID-Breast29”. This stands for Women’s cancer risk identification-Breast29. The new test looks at DNA methylation (the marks on the DNA) that are altered with increasing cell division and age specifically in the luminal progenitor cells and can be measured from breast biopsies. This way, it can be evaluated how many “aged” cells are present in breast tissue.
Taking aim at progesterone
Higher lifetime levels of progesterone have previously been associated with a higher risk for breast cancer, possibly at least in part via its above-described action on cells in the breast. In our study, we looked at daily levels of oestrogen and progesterone throughout the menstrual cycle using saliva testing in women with and without alterations in the BRCA1 and BRCA2 genes. We found that women with genetic alterations in BRCA1 and BRCA2 had higher overall levels of the hormone progesterone than women without these genetic changes. Based on previous research, elevated progesterone levels may in part be a reason for the increased breast cancer risk in women with BRCA gene alterations. Blocking the action of progesterone could therefore help to reduce the cancer risk by reducing the number of “aged” cells in the breast.
Individual risk monitoring using epigenetics
To further look into this, we were fortunate to be able to work with volunteers in a clinical trial who either received a placebo or a drug that blocks the actions of progesterone called mifepristone for several months. Using the WID-Breast29 we found that mifepristone led to a slower turnover of luminal progenitor cells, indicating a potential reduction in cancer risk.
Interestingly, mifepristone reduced the WID-Breast29 in all volunteers without a BRCA gene alteration who are at average risk of breast cancer, but only in three quarters of the women with a BRCA gene alteration. The fact that some women with a BRCA gene alteration did not “respond” to the treatment with a reduction in the WID-Breast29 might indicate that they might require additional interventions to reduce their cancer risk – such as surgery.
Summary and next steps
Our study is the first to report daily hormone levels in women with and without BRCA gene alterations. We propose a new method for personalised risk monitoring and cancer prevention.
So far, we used breast biopsies to measure the WID-Breast29. While these have been extremely valuable for research, they are not suitable for repeat clinical monitoring of individual cancer risk over prolonged periods. Therefore, we now need to find out whether the WID-Breast29 – or similar epigenetic signatures – could be applied in other sample types that could be obtained more easily, for instance cervical samples or cheek swabs. Larger trials are also needed to see whether individualised risk monitoring reduce cancer cases and unnecessary surgical procedures.
We are grateful to everyone who contributed to this research, and in particular to the volunteers without whom this would not have been possible.
We hope that this and future research will help women to make informed and personalised decisions about their cancer risk.
You can find the research paper on this link.
By Chiara Herzog, Ph.D. (twitter: @chiara_herzog)