The Breast Cancer 1 Gene (BRCA1) Plays a Role in the Regulation of Human Mammary Stem Cell Self Renewal and Differentiation
9 May, 2007 01:07 pm
Stem cells are specialized cells that continually generate progeny cells for organ formation and maintenance. Stem cells can be found within the different tissues of the human body at all stages of life, before and after birth. It has recently been suggested that human breast cancers may arise from transformation of early stem and progenitor cells.
BRCA1 is a well-known tumor suppressor gene that was first identified in 1994. Women who carry germline mutations in one copy of BRCA1 have a lifetime risk of breast cancer as high as 80-85% in addition to a 30% risk of developing ovarian carcinoma. The propensity for carcinogenesis in these hormone dependent organs remains unexplained. However, the BRCA1 tumor phenotype is similar to the one we have proposed characterizes mammary stem cells and suggests that BRCA1 might play a role in breast stem cell function.
To investigate the role of the BRCA1 gene in stem cells, we developed a lentivirus, which carried small interfering RNA segments that, in effect, silences the BRCA1 gene. We then observed how the mammary stem cells functioned without the functional BRCA1. When BRCA1 was inhibited, the number of stem cells was increased by 75 percent. Furthermore, 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.
In order to demonstrate the clinical relevance of these findings we determined whether stem cell expansion was also characteristic of breast tissue obtained from known BRCA1 mutation carriers. In 5 of the 13 samples we detected clusters of ALDH1+ cells comprising entire acini (the sac-like part of the milk-producing glands in the breast). Importantly, these acini were histologically completely normal. No such expanded stem cell acini were found in any of 10 breast samples obtained from normal women. Furthermore, we found that expansion of ALDH1+ stem cells resulted from loss of BRCA1 expression.
We suggest that early events in carcinogenesis in BRCA1 may involve loss of the functional BRCA1 at this site leading to expansion of an abnormal stem cell pool which can then serve as targets for further mutations producing a tumor. These studies have important implications for an understanding carcinogenesis of hereditary breast cancer as well as having potentially important clinical implications for early diagnosis and prevention in these women.