Breast Stem Cells and Their Implications for Cancer

PL05-02 Interest in mammary stem cells (MaSCs) has been stimulated by their potential role in breast tumorigenesis. We have isolated discrete populations of mouse mammary epithelial cells on the basis of expression of the cell surface markers (CD29 and CD24) and transplanted these into cleared fat pads of recipient mice to identify the mammary stem cell. A population that expresses ‘basal’ markers and is highly enriched for mammary stem cells was defined. An absolute expansion in the number of mammary stem cells was observed in the pre-neoplastic phase in the MMTV-wnt-1 mammary tumor model, suggesting that these tumors originate within mammary stem cells. Interestingly, the basal stem cell-enriched population was found to be ‘triple negative’ for ER, PR and ErbB2. This phenotype is reminiscent of human basal tumors, inferring that the mammary stem cell may be the ‘cell of origin’ for this poor prognosis subset. We have recently further subdivided the luminal epithelial cell-containing population on the basis of CD61 (β3-integrin) expression. The CD61+ subset contained luminal progenitors, as defined by colony forming assays, and is the earliest identified cell-type to express ER. Since the GATA-3 transcription factor is a key marker of ‘luminal’ breast tumors, we studied its role in normal mammary gland development. Utilising conditionally targeted mice, Gata-3 was found to be essential for mammary gland morphogenesis in both the embryo and adult. Gata-3 deficiency resulted in an expansion of CD61+ luminal progenitors and a concomitant block in epithelial differentiation in both virgin and pregnant glands. These findings provide evidence for the existence of an epithelial hierarchy within the mammary gland and reveal that GATA-3is a critical regulator of luminal cell differentiation. It is likely that high expression of GATA-3 in luminal tumors confers a favourable prognosis due to the promotion of differentiation. Conversely, GATA-3 loss could result in a more clinically aggressive phenotype.