A Long-Lived Luminal Subpopulation Enriched with Alveolar Progenitors Serves as Cellular Origin of Heterogeneous Mammary Tumors

• (Ad-)Wap-Cre-marked nulliparous mammary epithelial cells are CD61+ luminal cells
• They represent a subpopulation of luminal progenitors
• They are enriched with self-sustained, long-lived alveolar progenitors
• They may serve as the cellular origin of multiple breast cancer subtypes

SummaryIt has been shown that the mammary luminal lineage could be maintained by luminal stem cells or long-lived progenitors, but their identity and role in breast cancer remain largely elusive. By lineage analysis using Wap-Cre mice, we found that, in nulliparous females, mammary epithelial cells (MECs) genetically marked by Wap-Cre represented a subpopulation of CD61+ luminal progenitors independent of ovarian hormones for their maintenance. Using a pulse-chase lineage-tracing approach based on Wap-Cre adenovirus (Ad-Wap-Cre), we found that Ad-Wap-Cre-marked nulliparous MECs were enriched with CD61+ alveolar progenitors (APs) that gave rise to CD61− alveolar luminal cells during pregnancy/lactation and could maintain themselves long term. When transformed by different oncogenes, they could serve as cells of origin of heterogeneous mammary tumors. Thus, our study revealed a type of long-lived AP within the luminal lineage that may serve as the cellular origin of multiple breast cancer subtypes.

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