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The Role of the Microenvironment in Mammary Gland Development and Cancer

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The Role of the Microenvironment in Mammary Gland Development and Cancer Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press The Role of the Microenvironment in Mammary Gland Development and Cancer Kornelia Polyak1,2,3 and Raghu Kalluri4,5 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 2Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115 3Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 4Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115 5Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 Correspondence: [email protected] The mammary gland is composed of a diverse arrayof cell types that form intricate interaction networks essential for its normal development and physiologic function. Abnormalities in these interactions play an important role throughout different stages of tumorigenesis. Branching ducts and alveoli are lined by an inner layer of secretory luminal epithelial cells that produce milk during lactation and are surrounded by contractile myoepithelial cells and basement membrane. The surrounding stroma comprised of extracellular matrix and various cell types including fibroblasts, endothelial cells, and infiltrating leukocytes not only provides a scaffold for the organ, but also regulates mammary epithelial cell function via paracrine, physical, and hormonal interactions. With rare exceptions breast tumors initiate in the epithelial compartment and in their initial phases are confined to the ducts but this barrier brakes down with invasive progression because of a combination of signals emitted by tumor epithelial and various stromal cells. In this article, we overview the impor- tance of cellular interactions and microenvironmental signals in mammary gland develop- ment and cancer. he mammary gland is composed of a combi- microenvironment composed of extracellular Tnation of multiple cell types that together matrix (ECM) and various stromal cell types form complex interaction networks required (e.g., endothelial cells, fibroblasts, myofibro- for the proper development and functioning of blasts, and leukocytes). Large amount of data the organ. The branching milk ducts are formed suggest that cell-cell and cell-microenvironment by an outer myoepithelial cell layer producing interactions modify the proliferation, survival, the basement membrane (BM) and an inner polarity, differentiation, and invasive capacity luminal epithelial cell layer producing milk dur- of mammary epithelial cells. However, the mol- ing lactation. The ducts are surrounded by the ecular mechanisms underlying these effects are Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey Rosen Additional Perspectives on Mammary Gland Biology available at www.cshperspectives.org Copyright # 2010 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a003244 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press K. Polyak and R. Kalluri poorly understood. The purification and com- differentiation of epithelial cells, and mammary prehensive characterization of each cell type epithelial cells form salivary gland–like struc- comprising normal and neoplastic human tures when placed on top of salivary gland breast tissue combined with hypothesis testing mesenchyme (Sakakura et al. 1979). This in cell culture and animal models are likely to differentiation-inducing effect of embryonic improve our understanding of the role these mesenchyme is so pronounced that it is able cells play in the normal functioning of the mam- to alter the phenotype of mammary carcinoma mary gland and in breast tumorigenesis. In this cells to a more benign differentiated state (De- article, we overview cellular and microenviron- Cosse et al. 1973, 1975). This could potentially mental interactions that play important roles be explained by the up-regulation of embryonic in the normal functioning of the mammary programs in the tumor cells and then their nor- gland and their abnormalities in breast cancer. malization in response to mesenchymal-derived differentiation inducing signals. Indeed, more recent studies have shown that the embryonic THE ROLE OF THE MICROENVIRONMENT IN morphogen Nodal is overexpressed in highly MAMMARY GLAND DEVELOPMENT AND metastatic breast cancer cells and in melano- FUNCTION mas. Nodal expression, and consequently the Contrary to that of most organs, the develop- invasive phenotype of the cancer cells, can be ment of the mammary gland mostly occurs down-regulated by placing the cells into human postnatally and it is only completed in adult- embryonic stem cell (hESC) microenvironment hood and some aspects of mammary epithelial (Postovit et al. 2008). cell differentiation even require the completion The importance of propercellularcontext for of a full-term pregnancy, lactation, and involu- normal mammary epithelial cell differentiation tion cycle. The mammary gland is also unique was also shown by the observation that cells as it is continuously remodeled following pub- plated on plastic tissue culture dishes displayed erty because of the cyclical influence of repro- very different phenotype and were not able to ductive hormones. Most of our knowledge of differentiate into milk producing mammary mammary gland development has been derived epithelium in contrast to cells plated in three- from observations made in mice and interpo- dimensional (3D) reconstituted basement lated for humans despite the well-known differ- membrane (Matrigel) cultures (Petersen et al. ences between human and mouse mammary 1992; Howlett and Bissell 1993). More recent gland development and function. Studies ad- follow up studies have shown that transition dressing human mammary gland development from monolayer to 3D cultures dramatically in- have been limited to the structural and immu- fluences the epigenetic programs of the cells, par- nohistochemical analyses of a limited number ticularly histone modification patterns (Le Beyec of samples collected at different stages of fetal, et al. 2007). Specifically, plating mammary epi- infantile, childhood, and pubertal development thelial cells in laminin-rich extracellular matrix (Anbazhagan et al. 1998; Osin et al. 1998; Nac- (Matrigel) induces rapid deacetylation of his- carato et al. 2000; Jolicoeur et al. 2003). tones H3 and H4 at the global level accompa- The mammary gland is derived from the nied with decreased overall transcription. ectoderm and in the human embryo the breast However, in the normal mammary gland bud arises as a result of proliferation of basal the majority of luminal epithelial cells are not cells of the epidermis because of factors secreted in direct contact with the basement membrane, by mesenchymal cells present in the breast bud but rather lay on top of myoepithelial cells (Anbazhagan et al. 1998). Mammary epithelial (Fig. 1). Myoepithelial cells influence the differ- cells remain responsive to signals emitted by entiation, polarity, proliferation, and invasion/ embryonic mesenchyme even to adulthood, migration of adjacent luminal epithelial cells. but only in nulliparous mice. In fact, signals They also produce the basement membrane emitted by embryonic mesenchyme dictate the (BM) that forms a physical barrier separating 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a003244 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press The Microenvironment of the Breast Leukocytes Fibroblasts Myoepithelial cell Luminal epithelial cell Endothelial cells Figure 1. Schematic view of a normal mammary duct and lobule. Black line indicates the basement membrane. In the ducts myoepithelial cells form a nearly complete layer around the luminal epithelial cells, whereas in the alveoli the myoepithelial layer is more fenestrated and some luminal epithelial cells can be in direct contact with the basement membrane. Yellow arrows indicate potential cell–cell and cell–matrix interactions. the epithelial and stromal compartments. Lu- basement membrane molecules such as laminin minal epithelial cells display apical-basal polar- 5 (Zahir et al. 2003). These results suggest that ity as shown by the localization of sialomucin cells that are embedded in 3D environment can (MUC1), epithelial specific antigen (ESA), and produce unique BM components that some- occludin on the apical membrane and integrin times resemble the in vivo conditions. b4 on the basolateral membrane. This polarity Besides myoepithelial cells, the effects of is observed in cell culture when luminal epi- numerous other stromal cell types have also thelial cells are grown in Matrigel but not in been tested in cell culture assays. For example, collagen I (Gudjonsson et al. 2002). However, co-culture of endothelial cells with MCF-7 coculture with normal myoepithelial cells re- breast cancer cells leads to apoptosis of endothe- stores luminal epithelial cell polarity even in lial cells and such apoptosis requires cell–cell collagen cultures and this is at least in part contacts. Although the functional impact of mediated by laminin-1 secreted by the myoepi- such studies remains to be elucidated, these thelial cells. Other studies have suggested that
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