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WIREs Dev Biol

Mammary gland development

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The mammary gland develops through several distinct stages. The first transpires in the embryo as the ectoderm forms a mammary line that resolves into placodes. Regulated by epithelial–mesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth. Subsequent stages of development—pubertal growth, pregnancy, lactation, and involution—occur postnatally under the regulation of hormones. Puberty initiates branching morphogenesis, which requires growth hormone (GH) and estrogen, as well as insulin‐like growth factor 1 (IGF1), to create a ductal tree that fills the fat pad. Upon pregnancy, the combined actions of progesterone and prolactin generate alveoli, which secrete milk during lactation. Lack of demand for milk at weaning initiates the process of involution whereby the gland is remodeled back to its prepregnancy state. These processes require numerous signaling pathways that have distinct regulatory functions at different stages of gland development. Signaling pathways also regulate a specialized subpopulation of mammary stem cells that fuel the dramatic changes in the gland occurring with each pregnancy. Our knowledge of mammary gland development and mammary stem cell biology has significantly contributed to our understanding of breast cancer and has advanced the discovery of therapies to treat this disease. WIREs Dev Biol 2012, 1:533–557. doi: 10.1002/wdev.35

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Figure 1.

Illustration depicting the stages of postnatal mammary gland development. At birth, the mammary epithelium is rudimentary, consisting of only a few small ducts that grow allometrically until puberty (4 weeks in mice). With the onset of puberty, comes expansive growth in a process called ductal morphogenesis that fills the fat pad with the epithelial mammary tree. This growth is influenced by growth hormone (GH), estrogen, and a growth factor, insulin‐like growth factor‐1 (IGF1). In the mature virgin, short tertiary branches form under the influence of progesterone, but alveologenesis only occurs upon pregnancy with the induction of prolactin (PRL), which together with progesterone, fuels the growth of alveolar cells. PRL stimulation continues into the stage of lactogenesis, culminating in milk production that continues until a lack of demand at weaning signals involution and the mammary gland is remodeled back to its original adult state.

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Figure 2.

Illustration depicting the generation of the mammary milk line. The position and specification of the multilayered epithelial ridge, the milk line, in an embryo at E10.5. The milk line is apparent between the forelimbs and hindlimbs that demarcate the rostral and caudal extension of the line. Specification of the line requires early Wnt signaling in the epithelium and in the mesenchyme that flanks the milk line. Tbx3 expression is required at early time points vertically under the line, and it controls subsequent Wnt signaling within the line that is required for the development of mammary placodes. Tbx3 expression is regulated by fibroblast growth factor 10 (FGF10) that emanates from somites underlying the line, as well as Wnt signaling in the flank and bone morphogenetic protein 4 (BMP4) signaling localized at the ventral border. For details, see text. (Reprinted with permission from Ref 30. Copyright 2010 Cold Spring Harbor Laboratory Press)

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Figure 3.

A schematic representation portraying embryonic mammary gland development. Mammary placodes expand into a ball of cells that descends into the underlying mesenchyme. Parathyroid hormone‐related protein (PTHLH) signals from the epithelium to the mesenchyme to increase the expression of bone morphogenetic protein receptor‐1A (BMPR1A). Bone morphogenetic protein 4 (BMP4) expressed in the mesenchyme signals through BMPR1A to MSX2 and inhibits hair follicle formation at the developing nipple sheath. The mammary epithelium grows into a small, simple tree‐like structure containing an open lumen and remains in this form until birth. For details, see text. (Reprinted with permission from Ref 30. Copyright 2010 Cold Spring Harbor Laboratory Press)

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Figure 4.

Schematized view of the events occurring during pubertal development. Terminal end buds (TEBs) grow through the mammary fat pad, fueled by cell proliferation (diagram at the bottom). Growth hormone (GH) regulates cell proliferation by inducing the expression of insulin‐like growth factor‐1 (IGF1) in both the liver and mammary stroma. IGF1 acts, together with estrogen secreted from the ovary, to induce epithelial cell proliferation (diagram at the top). Estrogen signaling through its receptor (ESR1) acts via a paracrine fashion to stimulate the release of epidermal growth factor (EGF) family member, amphiregulin (AREG), which proceeds to bind its receptor on stromal cells and induce expression of FGFs. FGFs, in turn, to stimulate luminal cell proliferation. Other factors, such as TGFB1, Reelin (RELN), Slit2, and Netrin1 (NTN1) contribute to mammary architecture by either positively or negatively regulating cell proliferation or maintaining cell–cell interactions. For details, see text.

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Figure 5.

Schematized view of the events that generate lactation competence during pregnancy. Alveoli develop into milk‐secreting lobules regulated by prolactin (PRL) that works together with progesterone. Both hormones regulate transcriptional programs that include the control of Rankl TNFSF11), which signals in a paracrine fashion to stimulate proliferation by upregulating expression of target genes such as Cyclin delta 1 (Ccnd1) through the RANK receptor on neighboring cells. Progesterone stimulates secondary and tertiary branching, while PRL integrates many signals, including those from the extracellular matrix (ECM) by interacting with integrin through transmembrane, signal regulatory protein α (SIRPA). PRL transduces this information through pathways, such as those mediated by JAK2/STAT5, whose downstream targets include milk genes casein β (Csnb) and whey acidic protein (Wap). For details, see text.

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Figure 6.

Illustration depicting the two stages of mammary gland involution. Upon weaning, the gland is remodeled back to its prepregnancy state. Stage 1 is reversible and is regulated largely by STAT3, which is induced by leukemia inhibitory factor (LIF) and opposes pro‐survival STAT5 signaling by upregulating the expression of numerous proteins including: lysosomal proteases, cathepsins; insulin‐like growth factor binding protein5 (IGFBP5); and two regulatory isoforms of phosphatidylinositol 3 kinase, p50α (P50A) and p55α (P55A). Cell death and limited proteolysis of the extracellular matrix (ECM) occur during this stage as plasminogen (PLG) is converted to plasmin through the actions of plasma kallikrein (KLK1), yet the alveoli largely retain their shape. This changes during stage 2, which is irreversible and characterized by alveolar collapse and adipocyte differentiation. Matrix metalloproteinases (MMPs) are released from their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and collaborate with plasmin to return the mammary gland to its prelactation state by releasing growth factors (GFs) and remodeling the ECM. For details, see text.

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Figure 7.

A schematic representation of the stem cell hierarchy within the mammary gland. A stem cell divides symmetrically or asymmetrically to generate a bipotent progenitor cell that gives rise to both a luminal and myoepithelial cell progenitor. Studies suggest that luminal progenitors differentiate into cells that are restricted to either ductal or alveolar lineages and as yet unidentified intermediate cells may be required for terminal differentiation. In contrast, myoepithelial progenitors are thought to differentiate directly into myoepithelial cells. This illustration represents one interpretation of available data, but the true hierarchy is likely to be much more complex. For details, see text.

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Blanche Capel

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earned her Ph.D. at the University of Pennsylvania and has been at Duke University since 1993. She earned her endowed professorship, the James B. Duke Professor of Cell Biology, for the meaningful discoveries she has made since her postdoctoral work in genetics at the National Institute for Medical Research in London. The broad goal of the research in Dr. Capel’s laboratory is to characterize the cellular and molecular basis of morphogenesis – how the body forms. She uses gonadal (gender/sex) development in the mouse as her model system and investigates a gene she helped discover, Sry, the male sex determining gene. Gonad development is unique in that a single rudimentary tissue can be induced to form one of two different organs, an ovary or testis, and she is learning all she can about this central mystery of biology.

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