Control of mammary stem cell function by steroid hormone signalling

The ovarian hormones oestrogen and progesterone profoundly influence breast cancer risk(1-3), underpinning the benefit of endocrine therapies in the treatment of breast cancer(4). Modulation of their effects through ovarian ablation or chemoprevention strategies also significantly decreases breast cancer incidence(5,6). Conversely, there is an increased risk of breast cancer associated with pregnancy in the short term(7). The cellular mechanisms underlying these observations, however, are poorly defined. Here we demonstrate that mouse mammary stem cells (MaSCs)(8,9) are highly responsive to steroid hormone signalling, despite lacking the oestrogen and progesterone receptors(10). Ovariectomy markedly diminished MaSC number and outgrowth potential in vivo, whereas MaSC activity increased in mice treated with oestrogen plus progesterone. Notably, even three weeks of treatment with the aromatase inhibitor letrozole was sufficient to reduce the MaSC pool. In contrast, pregnancy led to a transient 11-fold increase in MaSC numbers, probably mediated through paracrine signalling from RANK ligand. The augmented MaSC pool indicates a cellular basis for the short-term increase in breast cancer incidence that accompanies pregnancy. These findings further indicate that breast cancer chemoprevention may be achieved, in part, through suppression of MaSC function.