Can we prevent breast cancer in women at high risk?
The researchers — from the Princess Margaret Cancer Centre in Toronto, Canada — describe how they discovered this in a paper due to be published in the Journal of Cell Biology.
Their findings represent a step forward in the development of "chemoprevention" for those at high risk for breast cancer.
"Currently," says study senior author Rama Khokha, a senior scientist at Princess Margaret Cancer Centre and professor of biophysics at the University of Toronto, "there are no standard of care preventative interventions for women at high risk of breast cancer."
Breast cancer and stem cells
Breast cancer arises when abnormal cells in breast tissue grow and spread. Although the majority of cases occur in women, men can also get it because they too have breast tissue.
In the United States, it is expected that during 2018 there will be a total of 330,080 new cases of breast cancer in women and about 2,550 in men.
Carrying certain gene mutations raises the risk of developing cancer. Specific mutations in the tumor suppressor genes BRCA1 and BRCA2, for example, greatly raise the risk of developing breast cancer.
Mammary gland stem cells are specialized progenitor cells that mature into luminal and basal cells. These are the two cell types that form the mammary gland, the milk-producing organ in the breast.
During menstruation and pregnancy, a surge in progesterone levels spurs an increase in basal and luminal stem cells, resulting in expansion of the mammary glands.
Epigenetic proteins are the underlying switches that trigger the stem cell proliferation in response to progesterone.
However, expansion of mammary gland stem cells and exposure to progesterone are also tied to breast cancer. Women who carry certain high-risk genes for breast cancer often have higher numbers of mammary gland stem cells.
Progesterone induces epigenome changes
For their study, Prof. Khokha and her team observed how mammary gland cells isolated from mice responded to being exposed to progesterone. They paid particular attention to changes in the proteins and epigenomes of the cells.
The epigenome is a collection of compounds that switch genes on and off in the cell; essentially, it controls which genetic instructions are carried out and when by attaching chemical tags to DNA.
The team discovered that exposure to progesterone triggered a massive switch-on of genes in mammary gland stem cells — particularly in those that make luminal cells.
Prof. Khokha claims that this made them believe that perhaps "drugs that inhibit these epigenetic regulatory proteins might suppress the proliferation of stem and progenitor cells in response to progesterone."
The scientists went on to test several "epigenetic inhibitors," many of which have already received regulatory approval for human use.
Tests in mice revealed that a number of epigenetic inhibitors were able to block the expansion of mammary gland stem cells and reduce their number.
One drug in particular held back tumor formation in rodents prone to develop breast cancer. This was decitabine, a compound that stops "methyltransferase enzymes" from placing tags on DNA.
The drug has already been approved as a treatment for a blood disorder called myelodysplastic syndrome.
Moving on from mice, the team then carried out tests on mammary gland stem cells taken from women with a high risk of breast cancer.
They found that decitabine and other epigenetic inhibitors had a marked effect on stem cells from individuals carrying high-risk BRCA1 mutations.
Decitabine was also effective at blocking proliferation of stem cells from patients with high-risk BRCA2 mutations.
Prof. Khokha says that this shows that the action of certain epigenetic molecules on mammary gland stem cells "is conserved between mice and humans," and that there is potential for developing "epigenetic therapies" as chemoprevention for human breast cancer.
"Although it is becoming increasingly clear that stem and progenitor cells underlie cancer development, we lack strategies to target these cells for chemoprevention."
Prof. Rama Khokha