Stem Cells and Cellular Origins of Mammary Gland: Updates in Rationale, Controversies, and Cancer Relevance

Abstract

Evidences have supported the pivotal roles of stem cells in mammary gland development. Many molecular markers have been identified to characterize mammary stem cells. Cellular fate mapping of mammary stem cells by lineage tracing has put unprecedented insights into the mammary stem cell biology, which identified two subtypes of mammary stem cells, including unipotent and multipotent, which specifically differentiate to luminal or basal cells. The emerging single-cell sequencing profiles have given a more comprehensive understanding on the cellular hierarchy and lineage signatures of mammary epithelium. Besides, the stem cell niche worked as an essential regulator in sustaining the functions of mammary stem cells. In this review, we provide an overview of the characteristics of mammary stem cells. The cellular origins of mammary gland are discussed to understand the stem cell heterogeneity and their diverse differentiations. Importantly, current studies suggested that the breast cancer stem cells may originate from the mammary stem cells after specific mutations, indicating their close relationships. Here, we also outline the recent advances and controversies in the cancer relevance of mammary stem cells.

Figure 1

(a) The postnatal mammary gland development is multistage. (b) Two distinct phenotypes of mammary epithelium in different developmental stages: the ductal (A) and alveolar (B) epithelium, both bilayered, with inner layer of luminal cells and outer layer of myoepithelial/basal cells. There are also milk-producing cells in the inner layer of alveolar epithelium.

Figure 2

Cellular fate mapping of MaSCs by lineage tracing in vivo. A simplified schematic depicts the existence of unipotent and multipotent MaSCs characterized with distinct cellular markers (embryonic MaSCs: K14+, Axin2+, Notch1, Blimp1+, and p63+; postnatal MaSCs for unipotent basal lineage: K14+, K5+, Lgr5+, Axin2+, p63+, and Acta2+; postnatal MaSCs for unipotent luminal lineage: K8+, Elf5, Prom1+, Notch1+, Notch3+, and Blimp1+; multipotent postnatal MaSCs: Axin2+, K5+, K14+, K19+, Lgr5+, Lgr6+, and Sox9+) and their distinct differentiations.