Cancer Stem Cells and Familial Cancer Risk for Breast Cancer

One of the most important current trends in cancer biology is the study of cancer stem cells. The cancer stem cell model holds that cancer originates in tissue stem cells, and that dysregulation of these cells underlies the development of the tumor. Also, the cancer stem cell model suggests that tumors contain a small population of cells with stem cell properties (self-renewal and limitless proliferation), that these cells are resistant to chemotherapy, and that these are the cells that cause the majority of relapses.

Another important concept in oncology is hereditary cancer. Although 1 in 8 women will develop breast cancer, it has long been known that women with a family history of breast cancer are more likely to develop breast cancer themselves than are women with no such history. This observation led to the discovery of breast cancer predisposition genes such as BRCA1. Women who inherit a mutated form of this gene from a parent have a lifetime risk of breast cancer that is greater than 90% and are also at increased risk of ovarian cancer.

An interesting paper published recently in Proceedings of the National Academy of Sciences shows how these two concepts are linked. This group, led by Max Wicha from University of Michigan, wanted to investigate whether BRCA1 plays a role in the biology of mammary stem cells. Their first step was to treat normal mammary cells in a way that dramatically reduces how much BRCA1 they make (by using small interfering RNA, siRNA, a tool to inhibit the activity of a specific gene). They found that decreasing the amount of BRCA1 substantially increases the number of cells with stem-cell-like properties. This shows that one role of BRCA1 is to limit the proliferation of mammary stem cells. Because mammary stem cells are the cells that give rise to breast cancer, limiting their proliferation is protective against developing breast cancer, and loss of this protection increases the risk of developing a tumor.

The scientists were able to examine breast tissue from 13 women who were known to have a mutation in BRCA1 and from 22 women with no family history of breast cancer. 5 of the 13 samples from the women with BRCA1 mutations contained “lobules” (clusters) of cells composed almost entirely of mammary stem cells, and none of the samples from the 22 control women had such lobules. 4 of the 5 women (80%) with these “stem cell lobules” went on to develop cancer in the 9 years after the samples were obtained, compared with only 2 of the 8 women (25%) with a BRCA1 mutation but no “stem cell lobules.” Although the number of women studied was small, this difference (80% vs. 25%) was statistically significant. This result supports the idea that the increased number of mammary stem cells seen in women with a BRCA1 mutation is an early step in breast cancer development.

Normal mammary stem cells can give rise to one of two cell types, called myoepithelial cells and luminal epithelial cells. The breast ducts are lined with luminal epithelial cells, and these are surrounded by a layer of myoepithelial cells. Both can give rise to breast cancer, and women with a mutation in BRCA1 are much more likely to develop a cancer of the myoepithelial cells. Interestingly, Wicha and his colleagues showed that loss of BRCA1 function (as would happen in a woman with a BRCA1 mutation) interferes with the ability of the mammary stem cells to develop into luminal epithelial cells, but still allows the generation of normal myoepithelial cells.

One of the other functions of BRCA1 is to help maintain the integrity of cellular DNA. Loss of BRCA1 function impairs the ability of cells to correct DNA damage and leads to the accumulation of mutations. These two functions of BRCA1 together go a long way toward explaining why women with a mutation in this gene are at such high risk of developing breast cancer in particular. Loss of BRCA1 function leads to an accumulation of mammary stem cells and of myoepithelial cells that are both impaired in their ability to correct DNA damage, resulting in an extraordinarily high risk of developing breast cancer.

These findings support the cancer stem cell hypothesis by suggesting that dysregulation of stem cell self-renewal and differentiation is important for both sporadic and inherited breast cancer. What remains is to determine the role of BRCA1 in normal ovarian function, because women with mutations in this gene are prone to ovarian cancer as well.