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WIREs Dev Biol
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Endocrine hormones and local signals during the development of the mouse mammary gland

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Most of mammary gland development occurs postnatally under the control of female reproductive hormones, which in turn interact with other endocrine factors. While hormones impinge on many tissues and trigger very complex biological responses, tissue recombination experiments with hormone receptor‐deficient mammary epithelia revealed eminent roles for estrogens, progesterone, and prolactin receptor (PrlR) signaling that are intrinsic to the mammary epithelium. A subset of the luminal mammary epithelial cells expresses the estrogen receptor α (ERα), the progesterone receptor (PR), and the PrlR and act as sensor cells. These cells convert the detected systemic signals into local signals that are developmental stage‐dependent and may be direct, juxtacrine, or paracrine. This setup ensures that the original input is amplified and that the biological responses of multiple cell types can be coordinated. Some key mediators of hormone action have been identified such as Wnt, EGFR, IGFR, and RANK signaling. Multiple signaling pathways such as FGF, Hedgehog, and Notch signaling participate in driving different aspects of mammary gland development locally but how they link to the hormonal control remains to be elucidated. An increasing number of endocrine factors are appearing to have a role in mammary gland development, the adipose tissue is increasingly recognized to play a role in endocrine regulation, and a complex role of the immune system with multiple different cell types is being revealed. WIREs Dev Biol 2015, 4:181–195. doi: 10.1002/wdev.172 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Signaling Pathways > Global Signaling Mechanisms Signaling Pathways > Cell Fate Signaling
Scheme of hypothalamus‐pituitary axis in endocrine system. The hypothalamus secretes releasing hormones (RH) to stimulate hormone secretion from the anterior pituitary. The anterior part of pituitary gland releases stimulating hormones (SH) including gonadotropins (FSH, LH), thyroid stimulating hormone (TSH), and adrenocorticotropic (ACTH) all of which control the activity of peripheral endocrine glands such as the ovaries, testes, the thyroid gland, and the adrenal cortex. In addition, the anterior part of the pituitary gland produces growth hormone (GH) and prolactin (Prl). The posterior lobe of the pituitary gland releases oxytocin and antidiuretic hormone (ADH), which are freed by nerve endings that stem from the hypothalamus. ADH acts on the kidney.
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Model of the role of PrlR signaling in the mammary epithelium. Binding of prolactin to its receptor induces JAK2 activation and STAT5 phosphorylation. Phosphorylated STAT5 dimerizes, translocates to nucleus and induces expression of milk proteins. Cyclind1, Igf2, and Rankl have been mapped genetically downstream of PrlR signaling and been shown to be required in alveologenesis. ELF‐5 is a central mediator of PrlR function but also induces expression of Stat5 and may be downstream of RANK.
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Model of the role of PR signaling in the mammary epithelium. During adulthood, progesterone acts on hormone receptor positive cells and induces release of RANKL, WNT4, and calcitonin, Cyclind1 may be both a direct and indirect downstream target as is inhibitor of DNA binding 4 (Id4).
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Model of the role of ERα signaling in the mammary epithelium. The mouse mammary ducts are a bilayered epithelium. The lumen is lined by luminal cells which in turn are surrounded an outer layer of myoepithelial/basal cells. The two layers are separated from the surrounding stroma by basal membrane. The stromal cells include adipocytes, fibroblasts, endothelial, and immune cells. TEBs consist of body cells surrounded by cap cells. During puberty, Amphiregulin mRNA expression is strongly induced by estrogen. Amphiregulin is cleaved and released by ADAM17 and activates the EGFR in stromal cells. In response, stromal cells may release FGF7 to signal back to the epithelium and elicit cell proliferation at TEBs. A requirement for FGFR1/2 signaling in the mammary epithelium has been revealed by genetic experiments. Expression of Wnt5a, Wnt5b, Wnt7b, desert hedgehog Dhh, and Ephrin‐A2 transcripts were enriched in TEB epithelium whereas Wnt2, Frizzled 1, and Ephrin‐B1 were enriched in TEB stroma. There is genetic evidence for a role of p190A RhoGAP, FoxA1, and Nrip1 in ductal elongation. CSF1 and HGFL were implicated in TEB formation and ductal elongation through their role in macrophage recruitment and activations.
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Generation of chimeric mammary epithelia. Cleared mammary fat pads are injected with a mixture of Pr−/− or Erα−/− mammary epithelial cells carrying simultaneously a LacZ or GFP marker and Wt cells to generate chimeric epithelia. Both Pr−/− or Erα−/− used on their own to reconstitute a cleared mammary fat pad will show clear developmental block. Intermingled in a 1:10 ratio with Wt cells normal mammary gland development occurs. Within the chimeric epithelial, the hormone receptor‐deficient mammary epithelial cells participate in all aspect of morphogenesis and express milk proteins. This indicates that the two steroid receptors act largely by paracrine signaling.
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Model of local GH action. PR+ luminal epithelial cells synthesize growth hormone (GH) in response to progesterone. Secreted GH acts on mammary stem cells via the GHR expressed on their cell surface.
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Mammary gland tissue recombination techniques. (a) In 3‐week‐old mice, the inguinal gland can be surgically cleared of endogenous epithelium to obtain a cleared fat pad. Contralateral cleared fat pads can be engrafted with mammary epithelium derived from either Erα−/− or Wt donors and will reconstitute. This reveals epithelial intrinsic phenotypes. (b) To assess the mammary stroma‐intrinsic role of a gene product, cleared fat pads are derived from a mutant (Mt) donor and engrafted with a piece of Wt mammary epithelium. The recombined gland is placed onto the abdominal wall of a Wt host.
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Hormonal control of mouse mammary gland development. Whole‐mount micrographs of inguinal mammary glands of C57Bl6x129Sv mice at different stages of mammary gland development illustrate critical stages in mammary gland development. Corresponding reproductive stages are depicted by light blue boxes. In the red boxes the key female reproductive hormones. Arrows indicate at which stages the respective downstream receptor mediated signaling is limiting. In the orange boxes at the top indicate other endocrine factors that have been implicated in mammary gland development but whose precise role remains to be determined. During puberty, the rudimentary ductal tree elongates under the influence of estrogen until the edges of the fat pad are reached and simple ductal system is established through bifurcations. Terminal end buds (TEBs) (arrows) are characteristic of the pubertal stage. In adulthood, the ductal complexity increases through progesterone‐induced side branching. Side branching is enhanced during early pregnancy. Alveoli develop later in pregnancy (asterisk), they will be fully distended by milk during lactation. LN, lymph node.
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