Lineage-Restricted Mammary Stem Cells Sustain the Development, Homeostasis, and Regeneration of the Estrogen Receptor Positive Lineage

Abstract

The mammary gland (MG) is composed of different cell lineages, including the basal and the luminal cells (LCs) that are maintained by distinct stem cell (SC) populations. LCs can be subdivided into estrogen receptor (ER)⁺ and ER^- cells. LCs act as the cancer cell of origin in different types of mammary tumors. It remains unclear whether the heterogeneity found in luminal-derived mammary tumors arises from a pre-existing heterogeneity within LCs. To investigate LC heterogeneity, we used lineage tracing to assess whether the ER⁺ lineage is maintained by multipotent SCs or by lineage-restricted SCs. To this end, we generated doxycycline-inducible ER-rtTA mice that allowed us to perform genetic lineage tracing of ER⁺ LCs and study their fate and long-term maintenance. Our results show that ER⁺ cells are maintained by lineage-restricted SCs that exclusively contribute to the expansion of the ER⁺ lineage during puberty and their maintenance during adult life.

Keywords: cancer cell of origin; cell hierarchy; epithelial differentiation; estrogen receptor; lineage tracing; luminal cells; mammary gland; mammary stem cells; stem cells; unipotent stem cells.