Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes

Abstract

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions.

Figure 1

Proposed spatial organization of the extracellular matrix (ECM) and integrin function during mammary gland branching morphogenesis. The composition of the ECM that surrounds developing ducts and the type of integrin that relays signals from the ECM would depend on the morphogenic event. Areas requiring invasion and proliferation and low adhesion (TEBs [terminal end buds], side branching) would have a unique ECM/integrin profile compared with areas that are dormant (primary ducts, noninvasive end buds). Unique signals in areas that may require stem or progenitor cell differentiation may require specific ECM-integrin profiles, unlike other areas.

Figure 2

Mechanism by which matrix metalloproteinases (MMPs) can affect branching morphogenesis. 1. Proteolytic digestion of extracellular matrix (ECM) would alter ECM-integrin tethering and ECM-integrin signalling [47-48]. 2. Cleavage of ECM may produce soluble ECM fragments containing morphogenic activity [49-54]. 3. ECM-sequestered factors may be released to produce morphogenic gradients or signalling [52-54]. 4. Loss of cell–cell adhesion molecules by MMPs would lead to epithelial-to-mesenchymal transition and increased invasiveness [55-57]. 5. Ligand or receptor shedding might initiate autocrine, juxtacrine, or paracrine morphogenic signalling [58-59].

Figure 3

Proposed morphogenic mechanisms mediated by matrix metalloproteinases (MMPs) and MMP inhibitors. At sites of invasion and migration (TEBs [terminal end buds], lateral side branches, invasive end buds), MMP activity may induce a transient epithelial-to-mesenchymal transition (EMT), thereby allowing the tip to move forward. Alternatively, high levels of MMP inhibitors may force an 'ameboid-like' movement, independent of MMP activity, through the meshwork of the extracellular matrix [96].