Breast cancer linked to stem cells

It has long been a mystery why there is a significant increase in incidence of breast cancer associated with pregnancy.

It is known that sustained exposure to the hormones oestrogen and progesterone is a well-established risk factor for breast cancer, and that pregnant women experience elevated levels of these hormones, although the mechanism linking the two has remained elusive.

Now, researchers at the Walter and Eliza Hall Institute (WEHI) have found that these hormones cause an increase in the number of mammary stem cells (MaSCs) in mice, and these stem cells can mutate, leading to cancer.

Using mouse models, they showed that when the ovaries were removed or the animals were treated with hormone inhibitors (which are in clinical use as anti-breast cancer agents), breast stem cell numbers dropped and the cells appeared to become dormant.

The puzzling thing is that these MaSCs lack the receptors that would make them directly influenced by oestrogen and progesterone.

However, Dr Jane Visvader, from the WEHI, found that even without these receptors, the stem cells are remarkably influenced by the hormones.

Visvader, in collaboration with Dr Jack Martin at St Vincent’s Institute Melbourne and Dr Hisataka Yasuda at the Nagahama Institute for Biochemical Science, believe this is mediated through paracrine signalling from the RANK ligand.

The implication is that inhibiting the RANK ligand pathway might reduce the risk of breast cancer. Such inhibitors are already in clinical trials to help maintain bone strength and treat breast cancer that has spread to the bones.

“Our discovery suggests that inhibitors of RANK or other stem cell pathways represent possible therapeutic strategies that could also be investigated as breast cancer prevention agents,” Dr Lindeman said.

The research was supported by the Victorian Government through the Victorian Breast Cancer Research Consortium/Victorian Cancer Agency, Susan G. Komen Foundation, National Breast Cancer Foundation, National Health and Medical Research Council, the Australian Cancer Research Foundation and the Victorian Government's Operational Infrastructure Scheme.

The paper was published in Nature today.