by ecancer reporter Clare Sansom

It is widely recognised that mothers are at lower risk from breast cancer than women with similar characteristics who have never given birth. Conversely, however, pregnancy confers a short-term increase in the risk of the disease. These factors are indicators of the crucial role that the ovarian hormones, oestrogen and progesterone, play in breast cancer development; however, the molecular and cellular basis for this link is still poorly understood. Researchers from Melbourne, Australia have now shown that mouse mammary stem cells are highly responsive to signalling by oestrogen and progesterone.

The researchers isolated subsets of mammary epithelial cells from young adult female mice that had been ovariectomized and were thus no longer exposed to the hormone-driven oestrus cycle. A significant decrease in the number of repopulating stem cells in glands from ovariectomized mice compared to controls indicated that these cells are regulated by the ovarian hormones, despite lacking the receptors for these hormones. Glands from ovariectomized mice also differed in gene expression profile from those of controls, with decreased expression of cell cycle regulators and of some gene targets of oestrogen and progesterone.

The relative contribution of the two hormones to stem cell proliferation was tested by treating the mice with hormone pellets, and only a combination of the two hormones was found to increase proliferation. Preventing oestrogen biosynthesis by control mice by using the aromatase inhibitor letrozole had a similar effect to ovariectomy, whereas a progesterone antagonist had little effect on stem cell function. Significantly reduced numbers of mammary stem cells were also observed in aromatase knockout mice, which cannot synthesise oestrogen.

The researchers also monitored the mouse mammary stem cell population during pregnancy, and showed that stem cell numbers increased quickly until mid-pregnancy and then declined. These stem cells were not as proliferative as “normal” stem cells and also showed differences in their gene expression profiles. Despite these differences, however, this enhancement of the mammary stem cell pool, which increases the chance of clonal expansion of mutated cells, may explain the short-term increase in breast cancer risk that is associated with pregnancy.

Understanding the hormonal control of stem cell function has important implications for chemoprevention of breast cancer. The prolonged benefit of anti-oestrogen therapy may be explained at least partly by a decrease in the number and proliferative nature of mammary stem cells. Increased understanding of the nature of these stem cells and particularly methods by which they can be suppressed may lead to the development of further chemoprevention strategies.

Reference

Asselin-Labat, M-L, Vaillant, F., Sheridan, J.M. and 8 others (2010). Control of mammary stem cell function by steroid hormone signaling. Nature 465, 798-802. doi:10.1038/nature09027