Breast cancer stem cells and their role in resistance to endocrine therapy.

Developmentally, tumours can be viewed as aberrant versions of normal tissues. For example, tumours often retain differentiation markers of their tissue of origin. In addition, there is evidence that they contain cancer stem-like cells (CSCs) that drive tumourigenesis. In this review, we summarise current evidence that breast CSCs may partially explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly oestrogen receptor-α-negative (ER-). If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ER and can only respond to treatment by virtue of paracrine signalling from neighbouring, differentiated ER+ tumour cells. Normal breast epithelial stem cells are regulated by the epidermal growth factor receptor and other growth factor receptor signals. The observed increase in growth factor receptor expression in endocrine-resistant breast cancers may reflect a bigger proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ER- and EGR+/HER2+, which would support this view. It is reported that CSCs express mesenchymal genes, which are suppressed by ER expression, further indicating the mutual exclusion between ER+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ER in these cells in diverse breast tumour sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.