Article

Information networks in the mammary gland

Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 36.46). 10/2005; 6(9):715-25. DOI: 10.1038/nrm1714
Source: PubMed

ABSTRACT Unique developmental features during puberty, pregnancy, lactation and post-lactation make the mammary gland a prime object to explore genetic circuits that control the specification, proliferation, differentiation, survival and death of cells. Steroids and simple peptide hormones initiate and carry out complex developmental programmes, and reverse genetics has been used to define the underlying mechanistic connections.

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Available from: Gertraud W Robinson, Jul 29, 2015
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    • "The mammary gland is a very dynamic tissue which undergoes dramatic changes during different developmental phases (Hennighausen and Robinson, 2005). With such pleomorphic capability, different mammary epithelial cell populations with distinct specialized functions are continuously generated and replaced. "
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    ABSTRACT: Runx2 is best known as an essential factor in osteoblast differentiation and bone development but, like many other transcription factors involved in development, is known to operate over a much wider tissue range. Our understanding of these other aspects of Runx2 function is still at a relatively early stage and the importance of its role in cell fate decisions and lineage maintenance in non-osseous tissues is only beginning to emerge. One such tissue is the mammary gland, where Runx2 is known to be expressed and participate in the regulation of mammary specific genes. Furthermore, differential and temporal expression of this gene is observed during mammary epithelial differentiation in vivo, strongly indicative of an important functional role. Although the precise nature of that role remains elusive, preliminary evidence hints at possible involvement in the regulation of mammary stem and/or progenitor cells. As with many genes important in regulating cell fate, RUNX2 has also been linked to metastatic cancer where in some established breast cell lines, retention of expression is associated with a more invasive phenotype. More recently, expression analysis has been extended to primary breast cancers where high levels of RUNX2 align with a specific subtype of the disease. That RUNX2 expression correlates with the so called 'Triple Negative' subtype is particularly interesting given the known cross talk between Runx2 and estrogen receptor signalling pathways. This review summaries our current understanding of Runx2 in mammary gland development and cancer, and postulates a role that may link both these processes. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 06/2013; 228(6). DOI:10.1002/jcp.24285 · 3.87 Impact Factor
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    • "STAT5A and STAT5B, hereafter referred to as STAT5, are the main STAT proteins that transduce the effects of PRL in the mammary gland. Deletion of STAT5 causes an attenuation of mammary alveolar development and milk secretion (Hennighausen and Robinson, 2005). STAT5 also promotes cell-cycle progression and suppresses apoptosis, thus contributing to cellular transformation (Yu and Jove, 2004). "
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    ABSTRACT: Transforming growth factor β (TGFβ) is widely recognised as an important factor that regulates many steps of normal mammary gland (MG) development, including branching morphogenesis, functional differentiation and involution. Tif1γ has previously been reported to temporally and spatially control TGFβ signalling during early vertebrate development by exerting negative effects over SMAD4 availability. To evaluate the contribution of Tif1 γ to MG development, we developed a Cre/LoxP system to specifically invalidate the Tif1g gene in mammary epithelial cells in vivo. Tif1g-null mammary gland development appeared to be normal and no defects were observed during the lifespan of virgin mice. However, a lactation defect was observed in mammary glands of Tif1g-null mice. We demonstrate that Tif1 γ is essential for the terminal differentiation of alveolar epithelial cells at the end of pregnancy and to ensure lactation. Tif1 γ appears to play a crucial role in the crosstalk between TGFβ and prolactin pathways by negatively regulating both PRL receptor expression and STAT5 phosphorylation, thereby impairing the subsequent transactivation of PRL target genes. Using HC11 cells as a model, we demonstrate that the effects of Tif1g knockdown on lactation depend on both SMAD4 and TGFβ. Interestingly, we found that the Tif1γ expression pattern in mammary epithelial cells is almost symmetrically opposite to that described for TGFβ. We propose that Tif1γ contributes to the repression of TGFβ activity during late pregnancy and prevents lactation by inhibiting SMAD4.
    Development 11/2012; 140(1). DOI:10.1242/dev.085068 · 6.27 Impact Factor
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    • "When secreted into the circulation, pituitary Prl binds to the prolactin receptor (Prlr) and activates Jak2–Stat5 signaling, which is required for lobuloalveolar development in the mammary gland during pregnancy. Upon phosphorylation by Jak2, phospho-Stat5 translocates to the nucleus of mammary epithelial cells, where it regulates the transcription of target genes that mediate the dramatic pregnancy-induced changes that prepare the mammary gland for lactation (Hennighausen and Robinson 2005). Consistent with the central role of Stat5 in pregnancyinduced mammary development, mice in which the Prl, Prlr, Jak2, or Stat5 genes have been deleted display severe defects in mammary differentiation and lactogenesis that are accompanied by loss of Stat5 activation (Horseman et al. 1997; Ormandy et al. 1997; Cui et al. 2004; Wagner et al. 2004). "
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    ABSTRACT: Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl(-/-), Prlr(-/-), and Stat5(-/-) mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1(-/-);Akt2(+/-) mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.
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