Cellular Plasticity in Mammary Gland Development and Breast Cancer

Abstract

Cellular plasticity is a phenomenon where cells adopt different identities during development and tissue homeostasis as a response to physiological and pathological conditions. This review provides a general introduction to processes by which cells change their identity as well as the current definition of cellular plasticity in the field of mammary gland biology. Following a synopsis of the evolving model of the hierarchical development of mammary epithelial cell lineages, we discuss changes in cell identity during normal mammary gland development with particular emphasis on the effect of the gestation cycle on the emergence of new cellular states. Next, we summarize known mechanisms that promote the plasticity of epithelial lineages in the normal mammary gland and highlight the importance of the microenvironment and extracellular matrix. A discourse of cellular reprogramming during the early stages of mammary tumorigenesis that follows focuses on the origin of basal-like breast cancers from luminal progenitors and oncogenic signaling networks that orchestrate diverse developmental trajectories of transforming epithelial cells. In addition to the epithelial-to-mesenchymal transition, we highlight events of cellular reprogramming during breast cancer progression in the context of intrinsic molecular subtype switching and the genesis of the claudin-low breast cancer subtype, which represents the far end of the spectrum of epithelial cell plasticity. In the final section, we will discuss recent advances in the design of genetically engineered models to gain insight into the dynamic processes that promote cellular plasticity during mammary gland development and tumorigenesis in vivo.

Keywords: breast cancer; cellular plasticity; epithelial-to-mesenchymal transition; mammary gland development; mouse models; tumorigenesis.

Figure 2

Models of the mammary epithelial hierarchy. (A). Differentiation of lobular-restricted and ductal-limited progenitors from pluripotent mammary epithelial stem/progenitor cells (serial transplantation model); adapted from [16] (2005). (B). Epithelial lineage hierarchy model based on the expression of integrins and other selected cellular markers using flow cytometry; adapted from [21]. (C). Continuous progression model based on transcriptomic changes and epigenetic states; adapted from [31].

Figure 1

Changes in the identity of mature cells that portray plasticity in lineage hierarchies. (A). Dedifferentiation (B). Transdifferentiation, direct or indirect, via transient progression through a progenitor state; adapted from [4].

Figure 3

Molecular drivers and signaling pathways that orchestrate epithelial cell lineage determination and cellular plasticity. Cytokeratin 8 (CK8)-positive luminal epithelial cells can acquire basal cell characteristics through expression of TP63, WNT, and KRAS. Conversely, epithelial cells expressing basal cytokeratins (e.g., CK14) can transdifferentiate into luminal cells in response to NOTCH and PI3K signaling.

Figure 4

Continuous model of the development of mesenchymal-like claudin-low breast cancer. Tumors acquire varying degrees of claudin-low characteristics and progress into a distinct claudin-low tumor type that is uncoupled from other intrinsic molecular subtypes; adapted from [98]. According to this model, the claudin-low breast cancer subtype is the cellular and molecular manifestation of cellular plasticity.

Figure 5

Advances in the development of experimental models to study cellular plasticity in tumor initiation and progression. (A). Illustration of the epithelial cell lineage-dependent activation of the MMTV-LTR and Wap gene promoter that are used to target the expression of oncogenes to the mammary gland. Note that the activation of these regulatory elements is highest in the luminal epithelium and absent in the mammary stroma. Therefore, the expression of the oncogene is tethered to cells that retain epithelial characteristics as long as the cancer cells are dependent on the oncogene for their growth and survival. (B). Two experimental approaches to express oncogenes in the mammary epithelium in a cell differentiation-independent manner. In these models, the mammary epithelial cell lineage-dependent activation of oncogenes (or reporter genes for cell lineage tracing) is mediated by the transient expression of DNA recombinases (Cre, Flp) that activate oncogenic mutant alleles of an endogenous gene (left) or the expression of transgenes that activate oncogenes from a ubiquitously active promoter or gene locus (right). An advantage of the transgenic (exogenous) expression model is its versatility in that oncogenes can be expressed in a ligand-mediated (i.e., doxycycline-controlled) as well as differentiation-independent manner to study the roles of oncogenes in the maintenance of cellular plasticity (e.g., mesenchymal properties of the claudin-low breast cancer type).