The origin of breast tumor heterogeneity

Abstract

How breast diversity is generated is a fascinating and fundamental question with important clinical implications. It is clear that the diversity of phenotypes displayed by breast cancer cells reflects the array of cell types present in the disease-free breast epithelium, including luminal, basal and stem cells. Therefore, it is hypothesized that the molecular regulators governing normal development of the breast epithelium may double as engines of breast tumor diversity. In the past few years, a deepened understanding of the mammary epithelial hierarchy has prompted the search for the cellular precursors of breast tumors. At the same time, the use of novel experimental strategies including the new technology of massively parallel sequencing has provided insight into the origin and evolution of breast tumors. Here, we review the current understanding of the basis of the intrinsic subtypes and the sources of inter-tumor heterogeneity.

FIGURE 1. The mammary epithelial hierarchy

A simplified schematic depicting the known relationships between stem, progenitor, and mature cell populations with the mammary epithelium. Bipotent MaSCs have been identified in lineage tracing in both embryonic and adult glands. More recently, unipotent stem cells have also been identified in both the luminal and basal lineages. There is also evidence for a long-lived, multipotent alveolar progenitor cell population (PI-MECs) which expands during pregnancy and survives involution. However, recent evidence suggests this population may only contribute to the luminal alveolar lineage.

FIGURE 2. Cellular origins of luminal and basal tumors

A, Cell-of-origin model of breast tumor heterogeneity. In this model, luminal tumors arise from transformation of more committed progenitors, and maintain their differentiation during tumor progression. On the other hand, basal-like tumors arise from earlier progenitors or from unipotent luminal stem cells. B, Genetic mutation model. In this scenario, basal and luminal tumors can both arise in similar precursors but the nature of the oncogenic signal determines the eventual phenotype of the tumor.