Cells-of-Origin of Breast Cancer and Intertumoral Heterogeneity.

Both intrinsic and extrinsic mechanisms underpin the profound intertumoral heterogeneity in breast cancer. Increasing evidence suggests that the intrinsic characteristics of breast epithelial precursor cells may influence tumour phenotype. These "cells-of-origin" of cancer preside in normal breast tissue and are uniquely susceptible to mutagenesis upon exposure to distinct oncogenic stimuli. Notably, molecular profiling studies have revealed strong concordance between the gene expression profiles of breast cancer subtypes and discrete cell types within the normal breast epithelium. Further characterisation of cells-of-origin of breast cancer requires comprehensive delineation of the normal mammary stem cell hierarchy. To this end, mouse models have provided valuable tools for exploring stem and progenitor cell function and identifying potential targets of neoplastic transformation via in vivo lineage-tracing studies. Nonetheless, the murine mammary differentiation hierarchy does not fully recapitulate human biology, and complementary studies using patient-direct breast tissue are critical. There is also accumulating evidence that extrinsic factors such as the microenvironment of premalignant cells can influence tumour initiation, highlighting opportunities for targeting cancer cells-of-origin via deconvolution of the premalignant epithelial niche. Pertinently, the identification of premalignant clones and targetable molecular perturbations responsible for driving their oncogenic transformation has critical implications for disease management and prevention.