Discovery halts breast cancer stem cells

Breast cancer stem cells (CSCs), the aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated by oestrogen via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers were able to halt the expansion of breast CSCs, a finding that suggests a new drug therapy target. The study, done in mice, is published in the Proceedings of the National Academy of Sciences (PNAS) Early Edition this week.

'A critical aspect of our work was to discover that oestrogen could promote breast cancer growth by modulating the proportion of breast CSCs. Since CSCs were not directly sensitive to oestrogen, it wasn't clear how oestrogen could affect their numbers. However, we found that hormone-sensitive cancer cells can communicate with CSCs to regulate their numbers. By disrupting the interaction between cancer cell populations we were able to prevent tumour growth,' said Charlotte Kuperwasser, PhD, associate professor in the anatomy and cellular biology and radiation oncology departments at Tufts University School of Medicine, and member of the genetics and cell, molecular and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

'Interestingly, this signalling pathway involves many of the same players that control normal stem cell biology, raising a more general possibility that CSCs in other tumours might be regulated by the mechanisms guiding normal development,' said Kuperwasser.

Kuperwasser and colleagues from MIT and Harvard used a mouse model to examine the behaviour of cancerous human breast tissue with a method that mimics the human body more closely than standard mouse models. The researchers first examined oestrogen's effect on breast CSC growth, finding that oestrogen caused breast CSC numbers to increase by nearly 800 percent. Since few breast CSCs contain oestrogen receptors, the researchers suspected that oestrogen's actions were through a signalling mechanism from nearby cells that express the receptors.

'When nearby cells were exposed to oestrogen, they secreted 14 times more FGF9, a signalling protein that drives CSC proliferation. When we blocked the FGF pathway with a small molecule inhibitor, we saw loss of CSC growth, tumour spheres generation, and even tumour formation. We then linked FGF signalling to the Tbx3 signalling axis, which is also important for embryonic mammary gland development,' said first author Christine Fillmore, PhD, a 2009 graduate of the genetics program at the Sackler School and currently a research fellow in genetics at Children's Hospital Boston.

'These results show that interfering with this signalling pathway is a promising strategy for targeting breast CSCs. We are hopeful that the improved understanding of the mechanisms that promote breast CSCs will lead to the development of drugs that can be used to halt CSC proliferation,' said Kuperwasser.

Kuperwasser also leads a laboratory at the Molecular Oncology Research Institute (MORI) at Tufts Medical Centre, which is dedicated to the exploration of the molecular mechanisms of cancer and the translation of findings into the clinic.