β1 and β4 integrins: from breast development to clinical practice

Abstract

Following a highly dynamic and complex dialogue between the epithelium and the surrounding microenvironment, the mammary gland develops into a branching structure during puberty, buds during pregnancy, forms intricate polar acini during lactation and, once the babies are weaned, remodels and involutes. At every stage of menstrual and pregnancy cycles, interactions between the cells and the extracellular matrix (ECM) and homotypic and heterotypic cell–cell interactions give rise to the architecture and function of the gland at that junction. These orchestrated programs would not be possible without the important role of the ECM receptors, integrins being the prime examples. The ECM–integrin axis regulates many crucial cellular functions including survival, migration and quiescence; the imbalance in any of these processes could contribute to oncogenesis. In this review we spotlight the involvement of two prominent integrin subunits, β1 and β4 integrins, in cross-talk with tyrosine kinase receptors, and we discuss the roles of these integrin subunits in the biology of normal breast differentiation and as potential prognostic and therapeutic targets in breast cancer.

Figure 1

β1 and β4 integrins in normal mammary gland acini and in invasive breast tumors. (Left) Mammary gland acini consist of a polarized architecture with a pseudo-stratified epithelium, including a luminal epithelium and a myoepithelial layer covered by a basement membrane (BM). Epithelial cells display apico-basal polarity, a cobblestone-like morphology with cortical actin filaments and an apical lumen. In the myoepithelial cells, α6β4 integrin links the cytoskeleton intermediate filaments to the BM through the assembly of hemidesmosomes. β1 integrin heterodimers connect the extracellular matrix (ECM) components and their biochemical and physical cues to the actin cytoskeleton through the focal adhesion complex. (Right) Invasive breast tumors lose their organized architecture, bilayered epithelium and BM by upregulating matrix metalloproteinases. Tumor cells lack polarity, change cell shape and display actin protrusions, which mediate cell migration and invasion. α6β4 integrin is phosphorylated (P) following microenvironmental cues and relocates into an F-actin-rich protrusion after hemidesmosome disassembly. β1 heterodimers are localized in invasive protrusions assembled with focal adhesions.