Cellular Plasticity in Mammary Gland Development and Breast Cancer

Simple Summary For many decades, the cellular and molecular mechanisms that orchestrate the differentiation of epithelial subtypes in the mammary gland have been a focus of intense investigations. Despite the orderly development of epithelial lineages with specific functions, individual cells or clusters of cells can switch identities in response to stress conditions and during the onset and progression of breast cancer. This review provides a comprehensive overview of factors that promote cellular plasticity. Changes in epithelial cell identity associated with pregnancy and lactation, inflammation, tissue repair, as well as the origin and progressive development of breast cancer subtypes discussed in this review demonstrate the broad impact of cellular plasticity on normal mammary gland development and the formation of malignant tumors.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.

Automated summary

Cellular plasticity, the ability of cells to change their identity, plays a crucial role in mammary gland development and breast cancer progression. This review provides a comprehensive overview of the factors and mechanisms that promote cellular plasticity in the mammary gland. It discusses changes in cell identity during normal development, the role of the gestation cycle, and highlights the importance of the microenvironment and extracellular matrix. The review also explores cellular reprogramming during mammary tumorigenesis, focusing on the origin of basal-like breast cancers and the role of oncogenic signaling networks. Additionally, recent advances in genetically engineered models to study cellular plasticity in vivo are discussed.