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

• Published in: Cell reports (Cambridge) 2017-08, Vol.20 (7), p.1525-1532
• Main Authors: Van Keymeulen, Alexandra, Fioramonti, Marco, Centonze, Alessia, Bouvencourt, Gaëlle, Achouri, Younes, Blanpain, Cédric
• Format: Article
• Language: English
• Subjects: Animals; cancer cell of origin; Cell Differentiation; cell hierarchy; Cell Lineage; Cell Tracking - methods; Doxycycline - pharmacology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial Cells - transplantation; epithelial differentiation; estrogen receptor; Female; Founder Effect; Gene Expression - drug effects; Homeostasis - genetics; lineage tracing; luminal cells; mammary gland; Mammary Glands, Animal - cytology; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; mammary stem cells; Mice; Mice, Transgenic; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Regeneration - genetics; Stem Cell Transplantation; stem cells; Stem Cells - cytology; Stem Cells - metabolism; unipotent stem cells
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.07.066

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. [Display omitted] •ER+ stem cells mediate expansion and maintenance of the ER+ lineage•ER+ stem cells expand and differentiate into ER+ cells following transplantation•ER+ stem cells survive involution and repopulate the ER+ lineage Van Keymeulen et al. performed lineage tracing of estrogen receptor (ER)-expressing cells in the mammary gland. They show that the ER+ cells are maintained by lineage-restricted stem cells that exclusively contribute to the expansion of the ER+ lineage during puberty and to their maintenance during adult life.