Tissue polarity-dependent control of mammary epithelial homeostasis and cancer development: an epigenetic perspective

Abstract

The basoapical organization of monolayered epithelia is defined by the presence of hemidesmosomes at the basal cellular pole, where the cell makes contacts with the basement membrane, and tight junctions at the opposite apical pole. In the mammary gland, tight junctions seal cell-cell contacts against the lumen and separate the apical and basolateral cell membranes. This separation is critical to organize intracellular signaling pathways and the cytoskeleton. The study of the impact of the highly organized apical pole, and notably apical polarity regulators (Crb complex, Par complex, and Scrib, Dlg, Lgl proteins) and tight junction proteins on cell phenotype and gene expression has revealed an intricate relationship between apical polarity and the cell nucleus. The goal of this review is to highlight the role of the apical pole of the tissue polarity axis in the epigenetic control of tissue phenotype. The organization of the apical pole and its importance in mammary homeostasis and tumorigenesis will be emphasized before presenting how apical polarity proteins impact gene expression indirectly, by influencing signal transduction and the location of transcription regulators, and directly, by participating in chromatin-associated complexes. The relationship between apical polarity and cell nucleus organizations might explain how apical polarity proteins could switch from nuclear repressors to nuclear promoters of cancerous behavior following alterations in the apical pole. The impact of apical polarity proteins on epigenetic mechanisms of gene expression will be discussed in light of increased evidence supporting a role for apical polarity in the fate of breast neoplasms.

Figure 1

Organization of the polarity complexes. At the apical side interactions among apical polarity regulatory proteins of the Crb, PAR and Scrib groups and tight junction (TJ) and adherens junction (AJ) proteins stabilize the apical junctional complex (AJC). Interactions of apical polarity proteins with elements of the cytoskeleton and signal transduction networks connect the AJC to other compartments in the cell. HD: hemidesomsomes that make contact with extracellular basement membrane proteins. Although a number of integrins make contact with extracellular matrix molecules, only α6-β4 integrin dimers forming the hemidesmosomes have been linked to basal polarity in breast epithelial cells.

Figure 2

Diagram of some of the possible ligands of ZO proteins within the apical junctional complex. ZO-1 can heterodimerize either with ZO-2 or with ZO-3. Proteins indicated in black in a dark gray circle are involved in cytoskeleton organization. Links to specific pathways (labeled in white in the darkest gray circles) important for breast cancer development are shown by discontinuous arrows. Of note: ZO-1 interacts with Cdc42 which is part of the PAR complex and LPP interacts with VASP and apical polarity regulatory protein Scrib.

Figure 3

The action of apical polarity proteins in the cell nucleus depends on the integrity of the apical junctional complex (AJC). If the AJC is intact, certain apical polarity proteins (APP) shuttle between nucleus and cytoplasm and participate in a repressive action on the transcription of genes that have to be silenced in order to maintain a differentiated, quiescent stage. Transcription regulators (TR) remain trapped within the AJC (top panel). If the AJC is disrupted (e.g., disturbed tight junctions) the release of a transcription regulator (TR) from the AJC might modify the local environment of certain genes. Apical polarity proteins can stay in the cell nucleus and their action on the new promoter environment now helps to promote gene transcription.

Figure 4

Effect of apical polarity alterations on the nucleus soil. The hypothesis is that the organization of the cell nucleus characteristic of normal, differentiated cells can be altered by modifications occurring at the level of the apical junctional complex (AJC). A specific modification leading to the release of a transcription regulator or the activation of a signal transduction pathway (e.g., type 1 or 2 alteration) might trigger changes in chromatin structure (e.g., via changes in DNA methylation and histone tail modifications) that affect different chromatin regions (e.g., via HMG proteins) thus, leading to a new nuclear organization (nucleus soil type A or B) (i.e., the new organization might correspond to changes in heterochromatin regions in the genome; this is represented by thick gray, convoluted ribbons in the cell nuclei in the drawing). The cell with nucleus soil type A might respond differently to certain incoming signals compared to a cell with nucleus soil type B. Therefore, future alterations and progression to cancer might be influenced by the initial modification(s) of the AJC.