BRCA-1 Involved In Breast Stem Cell Differentiation

Ann Arbor, MI -

The concept of a stem cell found within tumor populations that maintains the tumor mass has been around for more than a decade. Patents one using stem cells for screening of new cancer agents have driven the recent GSK-OncoMed deal that in total could be worth approximately $1.5 billion.

While it is obvious that tumor suppressor genes such as BCRA-1 are involved in the inhibition of tumor growth and therefore mutations in such genes are associated with cancer, one thing that is not so obvious is what these tumor suppressor genes do in normal, non-malignant stem cells. In a recent paper (Liu et al. CA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci U S A. 2008 Jan 29) scientists attempted to answer this exact question.

The researchers demonstrated that BRCA1 is needed for non-malignant mammary epithelial stem cells which are estrogen receptor negative to differentiate into estrogen receptor expressing luminal cells. A further demonstration of this was made when siRNA was used to inhibit expression of BRCA1 and the cells expressed higher levels of aldehyde dehydrogenase indicating retention of the stem cell phenotype.

Primary mammary tissues from females with congenital BRCA1 mutations was associated with epithelial cells expressing increased aldehyde dehydrogenase activity. Suggesting an in vivo example of the previously mentioned siRNA inhibition experiments.

These data suggest an interesting role for wild-type tumor suppressor genes in differentiation and the possibility that mutation of such genes is associated with resistance to differentiation and directly or indirectly oncogenesis.