A new study suggests that abnormal levels of female hormones in the bloodstream may be a reason why women with faulty BRCA1 and BRCA2 genes are more likely to develop breast and ovarian cancer over other cancers.
Researchers from the Department of Women’s Cancer at University College London (UCL) in the UK say their findings have already led to further research looking at new ways to prevent the cancers in women who are at higher risk.
It is now common knowledge that many women with faulty BRCA1 and BRCA2 genes – an inherited genetic alteration – are at higher risk of developing breast and ovarian cancer.
From this, many women make the difficult decision to have their breasts or ovaries removed as a way of prevention.
There has been much public focus on this over the last year, with actress Angelina Jolie revealing her decision to undergo a bilateral mastectomy as a result of a faulty BRCA gene.
However, the researchers note it has been unclear as to exactly how faulty BRCA1 and BRCA2 genes lead to the development of breast and ovarian cancers rather than other cancers.
Professor Martin Windschwendter, head of the Department of Women’s Cancer at UCL, told Medical News Today:
“Currently the accepted view is that the cancer risk for BRCA1 and BRCA2 alteration carriers is caused via a ‘local’ defect in the ability of normal cells to repair DNA damage, causing them to become malignant.”
“However,” he said, “this does not explain why BRCA1/2 mutation carriers are predisposed to develop breast and ovarian cancer specifically, rather than other types of cancer.”
For the study, published in The Lancet Oncology, the researchers used ultrasound scans to analyze the thickness of 1,966 uterus linings.
Of these, 1,573 measurements were from women who were negative for both faulty genes, and these were compared with 203 measurements from women positive for the faulty BRCA1 gene, and 190 positive for the faulty BRCA2 gene.
According to the researchers, the thickness of the uterus lining (endometrium) is partly dependent on the levels of the female hormones estradiol and progesterone – hormones that are already known to be risk factors for breast and ovarian cancer.
Therefore, concentration levels of these hormones were measured within the participant’s bloodstream.
Results of the analysis revealed that women who carried the abnormal BRCA1 and BRCA2 genes demonstrated higher concentrations of female hormones.
Furthermore, these differences in hormone levels were linked to differences in the thickness of the uterus lining within the second half of the menstrual cycle.
Prof. Windschwendter told Medical News Today:
“Our findings are strong circumstantial evidence that women with BRCA1/2 gene alterations are exposed to different levels of female hormones.
Because these hormones are already known risk-factors for breast and ovarian cancer, this is the likely explanation as to why BRCA1/2 carriers get breast and ovarian cancer rather than other types of cancer.”
Prof. Windschwendter says their work opens a new window of opportunity to prevent breast and ovarian cancer in BRCA mutation carriers.
Previous research from the team has shown that the hormone progesterone is triggered by an expression called RANKL, leading to the development of breast cancer.
A drug called Denosumab, which blocks RANKL expression, is already used in clinical practice to treat osteoporosis.
The researchers now anticipate that Denosumab could be suitable for use in a clinical trial for breast cancer prevention in BRCA mutation carriers.
Additionally, further investigation has already begun into how estrogen hormones affect the fallopian tubes, given that this is where most ovarian cancers begin in those who have BRCA mutations.
“Because it is now established that the far majority of ovarian cancers in BRCA1/2 carriers actually start in the Fallopian tubes,” said Prof. Windschwendter, “we have now started to look at how estrogens affect other genes in the tubes in order to design drugs which might prevent the carcinogenic effect of high levels of estrogens locally in the tube.”
The researchers note that these findings could mean women with BRCA mutations may not need to make such drastic decisions in the future, such as having their breasts or ovaries removed, to abolish their increased risk of such cancers.
However, when it comes to genetic factors regarding breast cancer, other research has challenged the findings from UCL.
Researchers from the University of Nebraska Medical Center (UNMC) and Creighton University suggest that each individual family has their own genetic factors that contribute to the development of breast cancer, which they say goes against the existing theory that “the same disease must have the same cause.”
According to the researchers, there are approximately 30 to 50 gene mutations that have been identified that affect around 30-40% of women – the most common being the BRCA mutations discovered 20 years ago.
For their study, published in The Breast Journal, the researchers analyzed and sequenced more than 20,000 genes in eight members of a family – of whom five were affected by breast cancer over three generations – and discovered a mutated gene called KAT6B.
According to the researchers, this gene is linked to many types of cancer, but not breast cancer. Through testing this same gene mutation in 40 other families with familial breast cancer, they found this particular gene mutation was not present.
Dr. Sam Ming Wang, associate professor at the Department of the Genetics, Cell Biology and Anatomy at UNMC, says:
“Our data shows that the same disease can have different causes. People have been focused on finding a common mutation among different families.
As many families have their own genetic causes, searching for a common cause will not work. This can explain why after almost 20 years we haven’t made significant progress.”
Medical News Today recently reported on a new imaging technique that may be able to identify breast cancer subtypes and early treatment response.