Appraisal of progenitor markers in the context of molecular classification of breast cancers

The Heisenberg uncertainty principle has a great impact on medical research by drawing our attention to the bias introduced by our experimental tools. In a recent issue of Breast Cancer Research, Keller and colleagues [1] report an example of this principle: sustained propagation of large numbers of cells, through the establishment of cell lines, disrupts the normal balance between differentiated cells and their progenitors, as observed in fresh biological specimens. The work of these authors contributes another piece in a contentious field that combines tissue morphology and immunohistochemical phenotypes [2,3], molecular classification of breast cancer tissues [4], and cell biological assays aimed at the tumor-initiating cell (TIC) phenotype [5]. Sorting cells according to their respective cell surface markers, CD44+/CD24-/low, results in the enrichment of TIC activities, including mammospheres [6] and transplantation efficiency in mouse xenografts [7]. Establishing xenograft growth could be the product of several system-specific selections other than breast progenitor phenotypes. However, further molecular profiling of these cell populations - in which CD44+/CD24-/low-sorted cells expressed low levels of luminal differentiation markers (such as MUC1, CD24, or CDH1) and elevated levels of epithelial-mesenchymal transition markers (such as VIM, collagens, TWIST1, SNAI1/2, and Zeb1/2) - indicated a link between epithelial-mesenchymal transition, TIC, and basal-like [6,8] or claudin-low [9,10]-specific breast cancer molecular subtypes. More recently, however, a more comprehensive interrogation of pluripotent self-renewal identified a population high for CD24, or luminal progenitors [9,11-13], capable of giving rise to mesenchymal or basal-like tumors, at least in the context of BrCa1 mutations. Given the variability of single markers within single individuals, the different sensitivities each cell biological assay presents with, and the consistency across other genes