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Review
. 2006;8(1):201.
doi: 10.1186/bcr1368. Epub 2005 Dec 5.

Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis

Mark D Sternlicht  1
Affiliations
Review

Key stages in mammary gland development: the cues that regulate ductal branching morphogenesis

Mark D Sternlicht. Breast Cancer Res. 2006.

Abstract

Part of how the mammary gland fulfills its function of producing and delivering adequate amounts of milk is by forming an extensive tree-like network of branched ducts from a rudimentary epithelial bud. This process, termed branching morphogenesis, begins in fetal development, pauses after birth, resumes in response to estrogens at puberty, and is refined in response to cyclic ovarian stimulation once the margins of the mammary fat pad are met. Thus it is driven by systemic hormonal stimuli that elicit local paracrine interactions between the developing epithelial ducts and their adjacent embryonic mesenchyme or postnatal stroma. This local cellular cross-talk, in turn, orchestrates the tissue remodeling that ultimately produces a mature ductal tree. Although the precise mechanisms are still unclear, our understanding of branching in the mammary gland and elsewhere is rapidly improving. Moreover, many of these mechanisms are hijacked, bypassed, or corrupted during the development and progression of cancer. Thus a clearer understanding of the underlying endocrine and paracrine pathways that regulate mammary branching may shed light on how they contribute to cancer and how their ill effects might be overcome or entirely avoided.

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Figures

Figure 1
Figure 1
Nuclear-stained wholemounts illustrating ductal branching morphogenesis of the abdominal (no. 4) mammary gland. (a) Embryonic day 18.5; (b) age 3 weeks; (c) age 4.5 weeks; (d) age 11 weeks. Ductal penetration into the mammary fat pad can be judged with respect to the nipple and/or main lactiferous duct (arrowhead), central lymph node (LN), distal LN (as seen in (d)) and fat pad margins. Terminal end buds are readily apparent in the growing 4.5-week gland, and short tertiary branches are apparent in the mature 11-week gland. Scale bars, 0.5 mm (a) and 1 mm (b–d).
Figure 2
Figure 2
Terminal end bud (TEB) and duct morphology. (a) High-magnification carmine alum-stained wholemount of a primary duct that has recently passed the central lymph node (upper left corner). The bifurcating TEB is in the final stages of forming two new primary ducts with independent TEBs. Three newly formed lateral (secondary) side-branches are also present along the trailing duct (open arrowhead), as is an area of increased cellularity that may represent a nascent lateral bud (filled arrowhead). Increased stromal cellularity is also apparent about the bifurcating TEB. Scale bar, 200 μm. (b) Immunophotomicrograph of a TEB illustrating its considerable proliferative activity, as indicated by the large number of cells that have undergone DNA replication and have thus incorporated bromodeoxyuridine (brown diaminobenzidine-stained nuclei) during a 2-hour chase period. Rather than pulling themselves forward, TEBs seem to be pushed through the adipose-rich stroma by virtue of this high proliferative activity [6]. Hematoxylin counterstaining also reveals the stromal collar, rich in fibroblasts and collagen, that characteristically surrounds the TEB neck (arrow) and its conspicuous absence beyond the invading distal cap. Scale bar, 100 μm. (c) Schematic diagram depicting the salient architectural features of TEBs and their subtending ducts, including their fibroblast-rich stromal collar and high mitotic index. Though there is no evidence that normal ductal cells ever cross the basal lamina, thinning of the basement membrane (dotted lines) does seem to occur at the tips of invading ducts as a result of their partial enzymatic degradation and/or incomplete de novo synthesis. Stromal macrophages and eosinophils are also depicted.
Figure 3
Figure 3
Provisional model depicting some of the key endocrine and paracrine signals that regulate mammary branching morphogenesis. ADAM, a disintegrin and metalloproteinase; AREG, amphiregulin; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FGF, fibroblast growth factor; FGFR, FGF receptor; GH, growth hormone; GHR, GH receptor; IGF, insulin-like growth factor; IGF1R, IGF-1 receptor; IGFBPs, IGF-binding proteins; MMP, matrix metalloproteinase; TEB, terminal end bud; TIMP, tissue inhibitor of metalloproteinases.
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