Abstract
The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. Here we show that Lgr6 marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lineage tracing analysis showed that Lgr6+ cells are unipotent progenitors, which expand clonally during puberty but diminish in adulthood. In pregnancy or following stimulation with ovarian hormones, adult Lgr6+ cells regained proliferative potency and their progeny formed alveoli over repeated pregnancies. Oncogenic mutations in Lgr6+ cells resulted in expansion of luminal cells, culminating in mammary gland tumours. Conversely, depletion of Lgr6+ cells in the MMTV-PyMT model of mammary tumorigenesis significantly impaired tumour growth. Thus, Lgr6 marks mammary gland progenitor cells that can initiate tumours, and cells of luminal breast tumours required for efficient tumour maintenance.
Highlights
The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity
We provide evidence that leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6)+ cells are unipotent progenitors that contribute to alveologenesis and function as tumour-initiating cell (TIC) for luminal mammary tumours
RNA sequencing of FACS-sorted Lgr6+ and Lgr6MECs showed differential expression of genes involved in mammary gland development (Fig. 1b)
Summary
The mammary gland is composed of a complex cellular hierarchy with unusual postnatal plasticity. The identities of stem/progenitor cell populations, as well as tumour-initiating cells that give rise to breast cancer, are incompletely understood. We show that Lgr[6] marks rare populations of cells in both basal and luminal mammary gland compartments in mice. Lgr[6] marks mammary gland progenitor cells that can initiate tumours, and cells of luminal breast tumours required for efficient tumour maintenance. The leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6) marks stem cells of taste buds[16], lung[17], and skin[18, 19], as well as rare mammary gland cells[18]. We traced the fate of Lgr6-positive (Lgr6+) cells during postnatal mammary gland formation, homeostasis, pregnancy, and in murine models of basal and luminal breast cancer. We provide evidence that Lgr6+ cells are unipotent progenitors that contribute to alveologenesis and function as TICs for luminal mammary tumours
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