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

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 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.

Prostate organogenesis: tissue induction, hormonal regulation and cell type specification

“…Early studies of ductal outgrowth during organogenesis and androgenmediated regeneration showed that cellular proliferation is highly enriched at ductal tips, suggesting a distal location for prostate epithelial progenitors (Sugimura et al, 1986a,b). Notably, a distal localization is consistent with the distribution of stem/progenitor cells during ductal outgrowth of tissues such as the lung and mammary gland (Hogan et al, 2014;Sreekumar et al, 2015). Furthermore, expression of Nkx3.1 is elevated in ductal tips (Kruithof-de Julio et al, 2013), and a role for Nkx3.1 in progenitor specification and maintenance has been suggested by the ductal morphogenesis defects in Nkx3.1 null mutants as well as by the stem cell properties of luminal Nkx3.1-expressing cells (termed CARNs; castration-resistant Nkx3.1-expressing cells) in the regressed adult prostate (Bhatia-Gaur et al, 1999;Wang et al, 2009).…”

Breast Cancer: Multiple Subtypes within a Tumor?

“…As pointed out in other reviews, [4, 32] clonal evolution and hierarchical heterogeneity are not mutually exclusive models, and are likely to be concurrently exerting their respective influences within breast tumors (Figure 3). Implicit in this view of multiple breast cancer subtypes is the potential for interactions between the disparate disease types, as applies generally to intra-tumoral heterogeneity (i.e.…”

“…In fact, there are reports of more differentiated luminal breast cancer cells exhibiting equal tumor initiating capacity as basal/stem-like breast cancer cells [13, 19]. Further insights and elucidation of the normal mammary hierarchy, which are extensively covered by these reviews [20, 21, 32], will be vital to the understanding of various distinct CSC populations in breast tumors. Additionally, comprehension of the intrinsic and niche factors that govern each of the normal mammary stem/progenitor cell states may shed light on the vulnerabilities of distinct CSC populations.…”

“…The idea that distinct breast cancer subtypes each correspond to a differentiation state of mammary cells represents a convergence point between normal mammary gland biology and breast cancer biology (Figure 1) [32, 34]. Although cancer cells of a particular differentiation state may only be ‘caricatures’ and not exactly resemble their normal counterparts [4], the ability to recognize a differentiation state that is most similar could still be helpful, just as with the stratification of patients based on intrinsic molecular subtypes [1].…”

“…Implicit in this view of multiple breast cancer subtypes is the potential for interactions between the disparate disease types, as applies generally to intra-tumoral heterogeneity (i.e. genetic clonal heterogeneity, epigenetic heterogeneity and noise-driven heterogeneity), which have been articulately reviewed [4, 32, 54]. These interactions may be cooperative, disruptive or neutral in nature, and instances of ‘altruistic’ clones which support the growth of breast tumors as a whole have been elegantly shown [55–57].…”