Patterns of cell signaling pathway activation that characterize mammary development

Andrechek, Eran R.; Mori, Seiichi; Rempel, Rachel E.; Chang, Jeffrey T.; Nevins, Joseph R.

doi:10.1242/dev.019018

Cited by 44 publications

(52 citation statements)

References 48 publications

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“…We complemented previous transcriptome studies of the adult MG (39)(40)(41)(42) by a transcriptional analysis of microdissected E13.5 embryonic MBs. MB pairs 2 and 3 were thus obtained, and their expression profiles were established by RNA-sequencing (RNAseq).…”

Section: Resultsmentioning

confidence: 98%

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Schep

Necşulea

Rodríguez-Carballo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Vertebrate Hox genes encode transcription factors operating during the development of multiple organs and structures. However, the evolutionary mechanism underlying this remarkable pleiotropy remains to be fully understood. Here, we show that Hoxd8 and Hoxd9, two genes of the HoxD complex, are transcribed during mammary bud (MB) development. However, unlike in other developmental contexts, their coexpression does not rely on the same regulatory mechanism. Hoxd8 is regulated by the combined activity of closely located sequences and the most distant telomeric gene desert. On the other hand, Hoxd9 is controlled by an enhancer-rich region that is also located within the telomeric gene desert but has no impact on Hoxd8 transcription, thus constituting an exception to the global regulatory logic systematically observed at this locus. The latter DNA region is also involved in Hoxd gene regulation in other contexts and strongly interacts with Hoxd9 in all tissues analyzed thus far, indicating that its regulatory activity was already operational before the appearance of mammary glands. Within this DNA region and neighboring a strong limb enhancer, we identified a short sequence conserved in therian mammals and capable of enhancer activity in the MBs. We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract.enhancers | TAD | mammalian development | mammary gland

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Section: Resultsmentioning

confidence: 98%

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Schep

Necşulea

Rodríguez-Carballo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The development of the APSU occurs in coordinated fashion, no doubt because of crosstalk between the differentiating epithelial cells and underlying mesenchyme, as well as differences in signaling pathways and receptors of the hair follicle, apocrine gland, and sebaceous gland (Hatsell and Cowin, 2006;Andrechek et al, 2008;Mayer et al, 2008). The apocrine gland duct typically opens into the infundibulum of the hair follicle, such that secretion contacts the hair shaft.…”

Section: The Evolution Of Mammary Secretionmentioning

confidence: 99%

The evolution of milk secretion and its ancient origins

Oftedal

2012

Animal

194

142

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Lactation represents an important element of the life history strategies of all mammals, whether monotreme, marsupial, or eutherian. Milk originated as a glandular skin secretion in synapsids (the lineage ancestral to mammals), perhaps as early as the Pennsylvanian period, that is, approximately 310 million years ago (mya). Early synapsids laid eggs with parchment-like shells intolerant of desiccation and apparently dependent on glandular skin secretions for moisture. Mammary glands probably evolved from apocrine-like glands that combined multiple modes of secretion and developed in association with hair follicles. Comparative analyses of the evolutionary origin of milk constituents support a scenario in which these secretions evolved into a nutrient-rich milk long before mammals arose. A variety of antimicrobial and secretory constituents were co-opted into novel roles related to nutrition of the young. Secretory calcium-binding phosphoproteins may originally have had a role in calcium delivery to eggs; however, by evolving into large, complex casein micelles, they took on an important role in transport of amino acids, calcium and phosphorus. Several proteins involved in immunity, including an ancestral butyrophilin and xanthine oxidoreductase, were incorporated into a novel membrane-bound lipid droplet (the milk fat globule) that became a primary mode of energy transfer. An ancestral c-lysozyme lost its lytic functions in favor of a role as a-lactalbumin, which modifies a galactosyltransferase to recognize glucose as an acceptor, leading to the synthesis of novel milk sugars, of which free oligosaccharides may have predated free lactose. An ancestral lipocalin and an ancestral whey acidic protein four-disulphide core protein apparently lost their original transport and antimicrobial functions when they became the whey proteins b-lactoglobulin and whey acidic protein, which with a-lactalbumin provide limiting sulfur amino acids to the young. By the late Triassic period (ca 210 mya), mammaliaforms (mammalian ancestors) were endothermic (requiring fluid to replace incubatory water losses of eggs), very small in size (making large eggs impossible), and had rapid growth and limited tooth replacement (indicating delayed onset of feeding and reliance on milk). Thus, milk had already supplanted egg yolk as the primary nutrient source, and by the Jurassic period (ca 170 mya) vitellogenin genes were being lost. All primary milk constituents evolved before the appearance of mammals, and some constituents may have origins that predate the split of the synapsids from sauropsids (the lineage leading to 'reptiles' and birds). Thus, the modern dairy industry is built upon a very old foundation, the cornerstones of which were laid even before dinosaurs ruled the earth in the Jurassic and Cretaceous periods.Keywords: evolution, lactation, milk composition, casein, milk fat globule ImplicationsLactation has an evolutionary origin and biological context within which its secretory processes and milk constituents evolved. This revi...

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“…Unsupervised clustering was performed with Cluster 3.0 and results were visualized with JavaTreeView. Pathway predictions were conducted as previously described (27). Additional signatures for HSF and Metastasis (IGS) were used as described (18).…”

Section: Dnamentioning

confidence: 99%

Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential

Andrechek

Cardiff

Chang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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120

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Human cancers result from a complex series of genetic alterations, resulting in heterogeneous disease states. Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity. Mouse models of cancer have generally been used to reduce this complexity and focus on the role of single genes. Nevertheless, our analysis of tumors arising in the MMTV-Myc model of mammary carcinogenesis reveals substantial heterogeneity, seen in both histological and expression phenotypes. One contribution to this heterogeneity is the substantial frequency of activating Ras mutations. Additionally, we show that these Myc-induced mammary tumors exhibit even greater heterogeneity, revealed by distinct histological subtypes as well as distinct patterns of gene expression, than many other mouse models of tumorigenesis. Two of the major histological subtypes are characterized by differential patterns of cellular signaling pathways, including ␤-catenin and Stat3 activities. We also demonstrate that one of the MMTV-Myc mammary tumor subgroups exhibits metastatic capacity and that the signature derived from the subgroup can predict metastatic potential of human breast cancer. Together, these data reveal that a combination of histological and genomic analyses can uncover substantial heterogeneity in mammary tumor formation and therefore highlight aspects of tumor phenotype not evident in the population as a whole.breast ͉ cancer ͉ genomics ͉ mouse

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Patterns of cell signaling pathway activation that characterize mammary development

Cited by 44 publications

References 48 publications

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

The evolution of milk secretion and its ancient origins

Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential

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