Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits?

From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis. In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ER alpha-. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ER alpha and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ER alpha+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ER alpha- and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ER alpha expression, further indicating the mutual exclusion between ER alpha+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ER alpha in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.