Abstract
IntroductionLineage tracing studies in mice have revealed the localization and existence of lineage-restricted mammary epithelial progenitor cells that functionally contribute to expansive growth during puberty and differentiation during pregnancy. However, extensive anatomical differences between mouse and human mammary tissues preclude the direct translation of rodent findings to the human breast. Therefore, here we characterize the mammary progenitor cell hierarchy and identify the anatomic location of progenitor cells within human breast tissues.MethodsMammary epithelial cells (MECs) were isolated from disease-free reduction mammoplasty tissues and assayed for stem/progenitor activity in vitro and in vivo. MECs were sorted and evaluated for growth on collagen and expression of lineages markers. Breast lobules were microdissected and individually characterized based on lineage markers and steroid receptor expression to identify the anatomic location of progenitor cells. Spanning-tree progression analysis of density-normalized events (SPADE) was used to identify the cellular hierarchy of MECs within lobules from high-dimensional cytometry data.ResultsIntegrating multiple assays for progenitor activity, we identified the presence of luminal alveolar and basal ductal progenitors. Further, we show that Type I lobules of the human breast were the least mature, demonstrating an unrestricted pattern of expression of luminal and basal lineage markers. Consistent with this, SPADE analysis revealed that immature lobules were enriched for basal progenitor cells, while mature lobules consisted of increased hierarchal complexity of cells within the luminal lineages.ConclusionsThese results reveal underlying differences in the human breast epithelial hierarchy and suggest that with increasing glandular maturity, the epithelial hierarchy also becomes more complex.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0453-3) contains supplementary material, which is available to authorized users.
Highlights
Lineage tracing studies in mice have revealed the localization and existence of lineage-restricted mammary epithelial progenitor cells that functionally contribute to expansive growth during puberty and differentiation during pregnancy
To characterize the mature luminal (ML), luminal progenitor cells (LPC), mature basal (MB), and basal progenitor cells (BPC) populations, mammary epithelial cells (MEC) were sorted based on EpCAM and CD49f expression and assessed for luminal and basal lineage markers (CK8 and CK14, respectively)
These results suggest that cytokeratin 8 (CK8) expression is not exclusively restricted to the luminal lineages in human MEC
Summary
Lineage tracing studies in mice have revealed the localization and existence of lineage-restricted mammary epithelial progenitor cells that functionally contribute to expansive growth during puberty and differentiation during pregnancy. Extensive anatomical differences between mouse and human mammary tissues preclude the direct translation of rodent findings to the human breast. Here we characterize the mammary progenitor cell hierarchy and identify the anatomic location of progenitor cells within human breast tissues. There are numerous differences between the human breast and the mouse mammary gland that preclude the direct translation of rodent studies to human breast development. The human breast is composed of 11 to 48 central ducts that radiate outward from the nipple [5], where circulating hormones and localized growth factors likely coordinate the growth of the terminal ductal lobular units (TDLU) that emanate from primary ducts. Mouse mammary glands are composed of a simple ductal tree that lack TDLU, and only exhibit strainspecific rudimentary alveolar budding in the absence of pregnancy. The anatomical and physiological equivalency of lobules and TDLU is unclear in the mouse
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