Axes of differentiation in breast cancer: Untangling stemness, lineage identity, and the epithelial to mesenchymal transition

Differentiation-associated regulatory programs are central in determining tumor phenotype, and contribute to heterogeneity between tumors and between individual cells within them. The transcriptional programs that control luminal and basal lineage identity in the normal mammary epithelium, as well as progenitor and stem cell function, are active in breast cancers, and show distinct associations with different disease subtypes. Also active in some tumors is the epithelial to mesenchymal transition (EMT) program, which endows carcinoma cells with mesenchymal as well as stem cell traits. The differentiation state of breast cancer cells is thus dictated by the complex combination of regulatory programs, and these can dramatically affect tumor growth and metastatic capacity. Breast cancer differentiation is often viewed along an axis between a basal-mesenchymal-stem cell state and a luminal-epithelial-differentiated state. Here we consider the links, as well as the distinctions, between the three components of this axis: basal versus luminal, mesenchymal versus epithelial, and stem cell versus differentiated identity. Analysis on a multidimensional scale, in which each of these axes is assessed separately, may offer increased resolution of tumor differentiation state. Cancer cells possessing a high degree of stemness would display increased capacity to shift between positions on such a multidimensional scale, and to acquire intermediate phenotypes on its different axes. Further molecular analysis of breast cancer cells with a focus on single-cell profiling, and the development of improved tools for dissection of the circuits controlling gene activity, are essential for the elucidation of the programs dictating breast cancer differentiation state.