Unraveling Heterogeneity in Epithelial Cell Fates of the Mammary Gland and Breast Cancer

Abstract

Fluidity in cell fate or heterogeneity in cell identity is an interesting cell biological phenomenon, which at the same time poses a significant obstacle for cancer therapy. The mammary gland seems a relatively straightforward organ with stromal cells and basal- and luminal- epithelial cell types. In reality, the epithelial cell fates are much more complex and heterogeneous, which is the topic of this review. Part of the complexity comes from the dynamic nature of this organ: the primitive epithelial tree undergoes extensively remodeling and expansion during puberty, pregnancy, and lactation and, unlike most other organs, the bulk of mammary gland development occurs late, during puberty. An active cell biological debate has focused on lineage commitment to basal- and luminal- epithelial cell fates by epithelial progenitor and stem cells; processes that are also relevant to cancer biology. In this review, we discuss the current understanding of heterogeneity in mammary gland and recent insights obtained through lineage tracing, signaling assays, and organoid cultures. Lastly, we relate these insights to cancer and ongoing efforts to resolve heterogeneity in breast cancer with single-cell RNAseq approaches.

Powerful quantifiers for cancer transcriptomics

“…3D organoids are also suitable to studying the spatial interactions between cells of the same or different phenotype[ 62 ]. The cellular heterogeneity of the organoids can be explored using single-cell RNA sequencing[ 63 ]. Instead of primary cultures, some investigators try to create 3D organoids from cancer patient derived xenografts[ 52 , 60 , 64 ].…”

Fine-tuning of Epithelial EGFR signals Supports Coordinated Mammary Gland Development

“…Capitalizing on FACS, we established that cocktails containing NGS Wnt/Rspo2 (“ RW ”) and EGF/NGS Wnt/Rspo2 (“ ERW ”) were roughly twice as efficient to sustain basal CD49f high /EpCAM medium cells compared to EGF alone (“ EGF ”) at day 5 ( Figure 5C ). This CD49f high /EpCAM medium population is described to contain stem cells (Samocha et al, 2019; Shackleton et al, 2006; Stingl et al, 2006). Further culture until day 13 in these three defined growth factor cocktails revealed three aspects; Firstly, only NGS Wnt/Rspo2 (“ RW ”) efficiently sustains basal cells (CD49f high /EpCAM medium ) over time.…”

“…The receptor signals that that govern the coordination of the outgrowth of epithelium during puberty in the mammary gland are still being defined. The EGFR (Epidermal Growth Factor Receptor) family consists of EGFR (ErbB1/Her1), ErbB2/Her2, ErbB3/Her3, and ErbB4/Her4 with ligands that include EGF, transforming growth factor-alpha (TGFα), and amphiregulin (AREG) (Hynes & Watson, 2010; Samocha, Doh, Kessenbrock, & Roose, 2019). Elegant mixed tissue- and transplantation-approaches into cleared fat pad defined an essential role for EGFR signaling in stromal cells to promote ductal development (Sebastian et al, 1998; Sternlicht et al, 2005; Wiesen, Young, Werb, & Cunha, 1999).…”

Morphology dynamics in intestinal crypt during postnatal development affect age-dependent susceptibility to radiation-induced intestinal tumorigenesis in Apc Min/+ mice: possible mechanisms of radiation tumorigenesis

“…Brenner et al reported the incidence of breast cancer in the Life Span Study of atomic bomb survivors and described that age at the menarche was a strong modifier of the radiation effect ( 49 ). The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle ( 50 ). These changes are fueled by dedicated stem and progenitor cells ( 50 ).…”

“…The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle ( 50 ). These changes are fueled by dedicated stem and progenitor cells ( 50 ). Although the detailed mechanism by which irradiation during sensitive periods might stimulate breast cancer development remains unknown, there is more support for changes in tissue composition and stem cell regulation after irradiation.…”