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.
Highlights
Simple in its form and function, the mammary gland requires a complex interplay of both intracellular and extracellular signals for its development into a branched glandular structure
The unanswered questions include: do interstitial extracellular matrix (ECM) and basement membrane (BM) act as single entities or do their individual components have distinct effects? What ECM receptors are used to transmit these signals, and how do ECM remodeling proteinases fit into these morphogenic events? In this review, we briefly summarize a vast amount of research that touches on these areas
Lung [4], kidney [5], salivary gland [6,7], and mammary gland [8,9] are examples of organs that develop through branching morphogenesis
Summary
Simple in its form and function, the mammary gland requires a complex interplay of both intracellular and extracellular signals for its development into a branched glandular structure. Through upregulation of MMPs, including MMP 3 [77] These culture studies, along with the transgenic work Determining the precise function of each ECM-degrading cited above, provide a role for MMP 3 and epimorphin as proteinase in branching morphogenesis is a time-consumtwo key morphogenic factors during mammary gland ing task, given their localization, activation, and interplay as 6 branching morphogenesis. Downmodulation of TIMP-1 by transgenic antisense expression in the mammary gland leads to increased branching and is associated with a loss of laminin in the ductal BM but not collagen type IV, suggesting that laminin degradation may provide a morphogenic signal [12].
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