Mammary gland development pathway - Embryonic development (Stage 1 of 4) (WP2813)

Homo sapiens

The mammary gland development can be subdivided into four stages of development: (1) embryonic development, (2) puberty, (3) pregnancy and lactation and (4) involution. In the embryonic development, a pair of mammary lines (ectoderm) arises, which gives origin to a pair of placodes. Then, each placode penetrates the underlying mesoderm. This results in the formation of the primary mammary gland [ 3]. NRG3 is a signal for placode formation. Besides that, it influences cell fate: it binds to its receptor, ERBB4, and induces MYC, which decreases expression of the integrins ITGA6 and ITGB1. The result is a change in cell adhesion and proliferation and consequent exit from the stem cell compartment [ 1]. Another process that should be highlighted in the embryonic development is the epithelial to mesenchymal transition (EMT). ZEB2 is an EMT regulator. It represses many genes (eg. CCND1, SFRP1, MIR200A, MIR200B, MIR429, TERT, CDH1, CLDN4 and ALPL), and also upregulates mesenchymal markers [ 2]. CCND1 and SFRP1 are related to cell proliferation, and SFRP1 are also related to WNT signaling pathway. MIR200A, MIR200B and MIR429 are microRNAs. TERT is responsible for elongation of telomere ends. CDH1 and CLDN4 are associated with cell adhesion, and ALPL may play a role in skeletal mineralization. Many genes modulate ZEB2. Some of these are shown in the figure [ 2]. TGFB1, TNF and IL1 are cytokines and AKT1 plays a role in many processes like cell proliferation, survival and growth. Hedgehog signals upregulate ZEB2 via TGFB1 [ 2].


Lab. Biodados UFMG , Kristina Hanspers , Jonathan Mélius , Denise Slenter , Egon Willighagen , and Eric Weitz


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Homo sapiens



Cell Type Ontology

milk secreting cell germ line stem cell

Pathway Ontology

regulatory pathway


Label Type Compact URI Comment
DNA Metabolite chebi:16991
MIR429 GeneProduct ensembl:ENSG00000198976
MIR200B GeneProduct ensembl:ENSG00000207730
MYC GeneProduct ensembl:ENSG00000136997
IL1 GeneProduct interpro:IPR000975
SFRP1 GeneProduct ensembl:ENSG00000104332
ITGA6 GeneProduct ensembl:ENSG00000091409
ALPL GeneProduct ensembl:ENSG00000162551
ZEB2 GeneProduct ensembl:ENSG00000169554
CLDN4 GeneProduct ensembl:ENSG00000189143
TERT GeneProduct ensembl:ENSG00000164362
ERBB4 GeneProduct ensembl:ENSG00000178568
ITGB1 GeneProduct ensembl:ENSG00000150093
TGFB1 GeneProduct ensembl:ENSG00000105329
NRG3 GeneProduct ensembl:ENSG00000185737
MIR200A GeneProduct ensembl:ENSG00000207607
CCND1 GeneProduct ensembl:ENSG00000110092
AKT1 GeneProduct ensembl:ENSG00000142208
CDH1 GeneProduct ensembl:ENSG00000039068
TNF GeneProduct ensembl:ENSG00000232810


  1. Stem cells and breast cancer: A field in transit. Smalley M, Ashworth A. Nat Rev Cancer. 2003 Nov;3(11):832–44. PubMed Europe PMC Scholia
  2. Neuregulin3 alters cell fate in the epidermis and mammary gland. Panchal H, Wansbury O, Parry S, Ashworth A, Howard B. BMC Dev Biol. 2007 Sep 19;7:105. PubMed Europe PMC Scholia
  3. Integrative genomic analyses of ZEB2: Transcriptional regulation of ZEB2 based on SMADs, ETS1, HIF1alpha, POU/OCT, and NF-kappaB. Katoh M, Katoh M. Int J Oncol. 2009 Jun;34(6):1737–42. PubMed Europe PMC Scholia