Integrins in mammary-stem-cell biology and breast-cancer progression--a role in cancer stem cells?

Abstract

Cancer cells with stem cell-like properties (cancer stem cells) are believed to drive cancer and are associated with poor prognosis. Data from mouse models have demonstrated that integrins, the major cellular receptors for extracellular-matrix components, have essential roles both during cancer initiation and progression, and during cell differentiation in normal development. By presenting an overview of the role of integrins in stem-cell biology and in cancer progression, this Commentary aims to present evidence for a role of integrins in the biology of cancer stem cells. Given the recent interest in the role of integrins in breast-cancer initiation and progression, we focus on the role of the members of the integrin family and their coupled signaling pathways in mammary-gland development and tumorigenesis.

Fig. 1.

The two main working models describing the generation of tumor heterogeneity. (A) The `cancer stem cell' model. Accumulation of genetic mutations in stem cells might lead to the formation of cancer cells with self-renewal properties (cancer stem cells). These cancer stem cells drive tumor progression and heterogeneity by proliferating and generating some differentiated cancer cells. (B) The `clonal evolution' model. In this model, epigenetic and genetic events can induce the transformation, dedifferentiation and acquisition of self-renewal properties in any cell type. The evolution of cancer cells that derive from the original cell is unstable, and depends on the surrounding environment and on paracrine signals that come either from stroma cells (green arrows) or from other tumor cells (brown arrows). The two models are not necessarily mutually exclusive.

Fig. 2.

The structure of the mammary epithelium. (A) Paraffin sections from a 10-week-old mouse mammary gland stained with hematoxylin-phloxin-safran dye. The surrounding fat pad is visible. (B) Paraffin section labelled with markers of epithelial luminal cells (anti-cytokeratin 8; green) and basal cells (anti-cytokeratin 14; purple). (C) Polarization of the luminal epithelium is illustrated by labeling for polarity markers zonula occludens 1 (ZO-1; apical, green) and β-catenin (βcat; basolateral, red). (D) Schematic representation of the structure of the mammary epithelium and the different integrin heterodimers expressed in luminal epithelial cells and myoepithelial cells.

Fig. 3.

Integrin expression and signaling in mammary stem and progenitor cells. (A) Representation of the adult mammary-stem-cell niche and the surface molecular markers expressed by stem- and progenitor-cells. Membrane receptors that have been implicated in mammary-stem-cell biology and the regulation of the stem-cell pool are also represented, including Frizzled, the epidermal and fibroblast growth factor receptors (EGFR and FGFR), Notch (with its ligand Delta present at the surface of adjacent niche cells) and the transforming growth factor β receptor (TGFβR). (B) The signaling role of β1 integrin in stem cells. β1 integrin (probably in association with α6 integrin) ensures the adhesion of mammary stem cells to the surrounding extracellular matrix of the niche, probably through the activation of the adhesion pathways that are classically associated with integrins (not represented here). In addition, β1 integrin influences the formation and orientation of the mitotic spindle during cell division. β1-integrin partners (such as ILK and paxillin) have been also implicated in this event. ILK is involved in two different types of protein complexes–one at focal adhesions, where ILK interacts with paxillin, α- and β-parvin, αPIX and Rac1 and regulates actin polymerization (Fielding et al., 2008a), and another at the centrosome (not represented). Although β1 integrin action might be dependent on ILK, it is currently unclear whether β1 integrin regulates one or both of these ILK pools. An independent (and speculative) interaction between the Notch receptor and β1 integrin is also represented–β1 integrin might modulate Notch activity by promoting its internalization through a caveolin-1-dependent process. (C) β1-integrin signaling during alveologenesis and alveolar differentiation. During pregnancy, prolactin begins to be produced and induces the amplification of alveolar progenitors, as well as their differentiation. Binding of prolactin to its receptor (Prolactin R) induces the activation of Janus kinase 2 (JAK2) and the subsequent phosphorylation of STAT5. In this event, β1 integrin appears to be essential to mediate the correct phosphorylation of STAT5. ILK and Rac1 are probably involved in this β1-integrin-associated signaling. Caveolin 1, which is associated with lipid-raft membrane domains, has been shown to downregulate both JAK2 and β1-integrin activity. In addition to promoting proliferation through STAT5, β1 integrin promotes cell-cycle progression by inducing the proteasomal degradation of the cyclin inhibitor p21CIP.