Cellular Plasticity and Heterotypic Interactions during Breast Morphogenesis and Cancer Initiation

Abstract

The human breast gland is a unique organ as most of its development occurs postnatally between menarche and menopause, a period ranging from 30 to 40 years. During this period, the monthly menstruation cycle drives the mammary gland through phases of cell proliferation, differentiation, and apoptosis, facilitated via a closely choreographed interaction between the epithelial cells and the surrounding stroma preparing the gland for pregnancy. If pregnancy occurs, maximal differentiation is reached to prepare for lactation. After lactation, the mammary gland involutes to a pre-pregnant state. These cycles of proliferation, differentiation, and involution necessitate the presence of epithelial stem cells that give rise to progenitor cells which differentiate further into the luminal and myoepithelial lineages that constitute the epithelial compartment and are responsible for the branching structure of the gland. Maintaining homeostasis and the stem cell niche depends strongly on signaling between the stem and progenitor cells and the surrounding stroma. Breast cancer is a slowly progressing disease whose initiation can take decades to progress into an invasive form. Accumulating evidence indicates that stem cells and/or progenitor cells at different stages, rather than terminally differentiated cells are the main cells of origin for most breast cancer subgroups. Stem cells and cancer cells share several similarities such as increased survival and cellular plasticity which is reflected in their ability to switch fate by receiving intrinsic and extrinsic signals. In this review, we discuss the concept of cellular plasticity in normal breast morphogenesis and cancer, and how the stromal environment plays a vital role in cancer initiation and progression.

Keywords: breast cancer; mammary gland; microenvironment; plasticity; stem cells; tumor initiation; tumor progression.

Figure 1

(A) The breast gland is composed of branching epithelial ducts that are embedded in collagen and fat-rich stroma. (B) These ducts terminate in the TDLU, the functional, milk-producing unit of the breast gland. Artwork in panel A is adapted from Patrick J. Lynch (CC BY 3.0). Red line depicts a virtual cut shown in panel C. (C) The TDLU is composed of acini and small ducts, joining together into larger ducts. The mammary tissue is embedded in a collagen-rich stroma, further embedded in a fatty connective tissue. The red box delineates the area magnified in panel D. (D) Mammary acini and ducts are arranged in double-layered structures. LEPs are situated towards the lumen, MEPs line the outside. Different cellular components within the breast gland can be characterized using identifying markers.

Figure 2

Schematic representation of selected breast tumor statistics, based on [55]. Lum = luminal, TN/BL = triple-negative/basal-like, HR = hormone receptor. Statistics adapted from [39,41], based on identifiable tumors.