Mutations in the well-known breast cancer susceptibility gene BRCA1 have a role in the propagation of aggressive stem cell-driven cancer.
The findings, according to researchers at the University of Michigan, offer further evidence that breast cancer treatment strategies require a stronger focus on the stem cells that drive the disease.
“Our lab previously identified the presence of mammary stem cells and, since BRCA1 is such a strong predictor of breast cancer, we were interested in the involvement of the gene in stem cells,” said Suling Liu, Ph.D., a researcher at the University of Michigan?s Comprehensive Cancer Center. “If mammary stem cells are, indeed, the driving force of breast cancer, then we need to know more about their function if we hope to create more effective therapies.”
To investigate the role of the gene in stem cells, the team engineered a lentivirus to carry small interfering RNA segments that, in effect, silence the BRCA1 gene. They then observed how a population of mammary stem cells functioned without the ability to produce BRCA1. When BRCA1 was inhibited, the number of stem cells was increased by 75 percent. These new cells, in turn, produced three times the normal amount of a stem cell marker protein ALDH1.
In an animal model of the disease, the knockdown of the BRCA1 gene increased the number of stem cells, which then propagated in the fatty tissues of the breast.
These studies suggest that loss of BRCA1 function leads to a block in cell differentiation, expanding the stem cell pool. Since BRCA1 also regulates DNA repair, this may then produce genetically unstable stem cells which in turn generate tumors in these women.
According to Liu, the loss of a single BRCA1 gene can lead to stem cell propagation. The researchers believe their findings might lead to better BRCA1 screening in women with a family history of breast cancer.