The mammary stem cell hierarchy: a looking glass into heterogeneous breast cancer landscapes - PubMed (original) (raw)

Review

. 2015 Dec;22(6):T161-76.

doi: 10.1530/ERC-15-0263. Epub 2015 Jul 23.

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Review

The mammary stem cell hierarchy: a looking glass into heterogeneous breast cancer landscapes

Amulya Sreekumar et al. Endocr Relat Cancer. 2015 Dec.

Abstract

The mammary gland is a dynamic organ that undergoes extensive morphogenesis during the different stages of embryonic development, puberty, estrus, pregnancy, lactation and involution. Systemic and local cues underlie this constant tissue remodeling and act by eliciting an intricate pattern of responses in the mammary epithelial and stromal cells. Decades of studies utilizing methods such as transplantation and lineage-tracing have identified a complex hierarchy of mammary stem cells, progenitors and differentiated epithelial cells that fuel mammary epithelial development. Importantly, these studies have extended our understanding of the molecular crosstalk between cell types and the signaling pathways maintaining normal homeostasis that often are deregulated during tumorigenesis. While several questions remain, this research has many implications for breast cancer. Fundamental among these are the identification of the cells of origin for the multiple subtypes of breast cancer and the understanding of tumor heterogeneity. A deeper understanding of these critical questions will unveil novel breast cancer drug targets and treatment paradigms. In this review, we provide a current overview of normal mammary development and tumorigenesis from a stem cell perspective.

Keywords: breast; cancer stem cells; cell signalling; mammary gland; stem cells.

© 2015 Society for Endocrinology.

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Conflict of interest statement

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Figures

Figure 1

Figure 1

Schematic illustration of the mammary epithelial cell hierarchy in a developmental context. A) This panel indicates 3 critical stages in the ontogeny of the mammary epithelium. (i) The mammary gland begins development as an invaginated bud in the embryo. Upon the onset of puberty, (iii) terminal end buds (TEBs) drive the rapid expansion of (ii) ductal structures through the fat in a proliferation dependent manner. TEBs (iii) comprise an outer layer of cap cells and multilayered body cells that are thought to largely give rise to basal and luminal cells respectively. During pregnancy, (iv) the epithelium proliferates and expands to form grape-like clusters of alveoli that secrete milk during lactation. Magnified snapshots of the (i) embryonic bud, (ii) ductal, (iii) TEB and (iv) alveolar structures indicate the complex and rapidly dynamic cellular compositions during different stages of mammary development. B) The cells observed spatially in their epithelial context in A) are displayed based on their position in the epithelial stem cell hierarchy as gleaned from lineage tracing data. Multipotent progenitors in the embryonic bud differentiate to generate all mature mammary lineages. In the adult, ducts are comprised of basal and luminal lineages. Lineage tracing data have identified cells in the basal compartment with bipotential capacity i.e. ability to give rise to both basal and luminal lineages. More recently, novel Notch2+ luminal populations were described whose origin and function remain ambiguous. Finally, studies in multiparous mice have identified long-lived progenitors termed Parity-Induced Mammary Epithelial Cells (PI-MECs) that are capable of initiating multiple rounds of alveologenesis during repeated pregnancies. Dotted lines indicate hypothesized derivative cell lineages in the epithelial hierarchy.

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