Mammary gland development pathway - Pregnancy and lactation (Stage 3 of 4) (WP2817)

Homo sapiens

The secondary mammary gland can be inactive or active. It becomes active during pregnancy and lactation, when there is a formation of alveoli, the structure responsible for milk production. There are four signal inputs for the mammary gland development during pregnancy and lactation: (1) prolactin receptor (PRLR), (2) epidermal growth factor receptors (ERBB1, ERBB2, ERBB3 and ERBB4), (3) estrogen receptors (ESR1 and ESR2) and (4) progesterone receptor (PGR). In the first case, PRL binds to PRLR, allowing its phosphorylation by JAK2, and the consequent coupling of STAT5 [ 1]. JAK2 phosphorylates STAT5, allowing its migration to nucleus. STAT5 target genes are related to proliferation (TNFSF11, CCND1), differentiation (CSN2, WFDC, ELF5, GJB2) and survival (BCL2L1) [ 1]. CEBPA and CEBPB are related to the balance between proliferation and differentiation of epithelial cells [ 2]. The TNFSF11/ TNFRSF11A pathway is associated with proliferation [ 1]. MYC, galanin and PTPN1 are regulators of the JAK2/STAT5 pathway and UFS are implicated in cell cycle control [ 1] [ 3] [ 4] [ 5]. In the second case, NRG binds to one of its receptors (ERBB1, ERBB2, ERBB3 or ERBB4) and the signal is transmitted by ERBB4 to STAT5, from where it follows as described above [ 1]. ERBB4 substitutes JAK2 by phosphorylating STAT5. Finally, in the last two cases, estrogen binds to its receptors, ESR1 and ESR2, and stimulates PGR [ 1]. ESR1, ESR2 and PGR are associated with proliferation. ESR1 also affects adhesion through induction of TTC9, which interacts with TPM3 (a protein associated with actin filaments), playing a role in involution [ 6]. PNCK appears to negatively regulate EGFR and MAPK signaling during pregnancy [ 7]. ATP2C2 is co-expressed with the component of Calcium influx channel encoded by ORAI1. Together, they regulate Ca2+ uptake, influencing differentiation and supporting the large calcium transport requirements for milk secretion during lactation [ 8].


Lab. Biodados UFMG , Kristina Hanspers , Jonathan Mélius , Denise Slenter , Egon Willighagen , Martina Summer-Kutmon , Finterly Hu , and Eric Weitz


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Homo sapiens



Cell Type Ontology

milk secreting cell

Pathway Ontology

regulatory pathway


Label Type Compact URI Comment
Estrogen Metabolite chebi:4903
DNA Metabolite chebi:16991
Oxytocin Metabolite wikidata:Q169960
Progesterone Metabolite chebi:17026
DNA Metabolite chebi:16991
DNA Metabolite chebi:16991
DNA Metabolite chebi:16991
DNA Metabolite chebi:16991
DNA Metabolite chebi:16991
DNA Metabolite chebi:16991
ORAI1 GeneProduct ensembl:ENSG00000276045
ERBB2 GeneProduct ensembl:ENSG00000141736
CCND1 GeneProduct ensembl:ENSG00000110092
PGR GeneProduct ensembl:ENSG00000082175
YY1 GeneProduct ensembl:ENSG00000100811
PRL GeneProduct ncbigene:5617
Galanin GeneProduct ncbigene:51083
TTC9 GeneProduct ensembl:ENSG00000133985
TPM3 GeneProduct ensembl:ENSG00000143549
BCL2L1 GeneProduct ensembl:ENSG00000171552
TNFSF11 GeneProduct ensembl:ENSG00000120659
ERBB1 GeneProduct ncbigene:1956
EIF4E GeneProduct ensembl:ENSG00000151247
MYC GeneProduct ensembl:ENSG00000136997
PNCK GeneProduct ensembl:ENSG00000130822
PTPN1 GeneProduct ensembl:ENSG00000196396
EGFR GeneProduct ensembl:ENSG00000146648
ELF5 GeneProduct ensembl:ENSG00000135374
STAT5 GeneProduct interpro:IPR035858
IKKA GeneProduct ncbigene:1147
CAV1 GeneProduct ensembl:ENSG00000105974
MAPK GeneProduct eccode:
CCND1 GeneProduct ensembl:ENSG00000110092
ESR2 GeneProduct ensembl:ENSG00000140009
JAK2 GeneProduct ensembl:ENSG00000096968
GJB2 GeneProduct ensembl:ENSG00000165474
STAT5 GeneProduct interpro:IPR035858
ERBB4 GeneProduct ensembl:ENSG00000178568
ERBB3 GeneProduct ensembl:ENSG00000065361
CSN2 GeneProduct ensembl:ENSG00000135222
ESR1 GeneProduct ensembl:ENSG00000091831
USF2 GeneProduct ensembl:ENSG00000105698
CEBPA GeneProduct ensembl:ENSG00000245848
BCL2L1 GeneProduct ensembl:ENSG00000171552
EIF4G GeneProduct interpro:IPR036211
CEBPB GeneProduct ensembl:ENSG00000172216
ATP2C2 GeneProduct ensembl:ENSG00000064270
NR3C1 GeneProduct ensembl:ENSG00000113580
TNFRSF11A GeneProduct ensembl:ENSG00000141655
Galanin GeneProduct ncbigene:51083
PRLR GeneProduct ensembl:ENSG00000113494


  1. Composite response elements mediate hormonal and developmental regulation of milk protein gene expression. Rosen JM, Zahnow C, Kazansky A, Raught B. Biochem Soc Symp. 1998;63:101–13. PubMed Europe PMC Scholia
  2. Diminished milk synthesis in upstream stimulatory factor 2 null mice is associated with decreased circulating oxytocin and decreased mammary gland expression of eukaryotic initiation factors 4E and 4G. Hadsell DL, Bonnette S, George J, Torres D, Klimentidis Y, Gao S, et al. Mol Endocrinol. 2003 Nov;17(11):2251–67. PubMed Europe PMC Scholia
  3. Developmental stage determines the effects of MYC in the mammary epithelium. Blakely CM, Sintasath L, D’Cruz CM, Hahn KT, Dugan KD, Belka GK, et al. Development. 2005 Mar;132(5):1147–60. PubMed Europe PMC Scholia
  4. Information networks in the mammary gland. Hennighausen L, Robinson GW. Nat Rev Mol Cell Biol. 2005 Sep;6(9):715–25. PubMed Europe PMC Scholia
  5. Pregnancy-upregulated nonubiquitous calmodulin kinase induces ligand-independent EGFR degradation. Deb TB, Coticchia CM, Barndt R, Zuo H, Dickson RB, Johnson MD. Am J Physiol Cell Physiol. 2008 Aug;295(2):C365-77. PubMed Europe PMC Scholia
  6. The local microenvironment instigates the regulation of mammary tetratricopeptide repeat domain 9A during lactation and involution through local regulation of the activity of estrogen receptor α. Shrestha S, Cao S, Lin VCL. Biochem Biophys Res Commun. 2012 Sep 14;426(1):65–70. PubMed Europe PMC Scholia
  7. Protein tyrosine phosphatase 1B restrains mammary alveologenesis and secretory differentiation. Milani ES, Brinkhaus H, Dueggeli R, Klebba I, Mueller U, Stadler M, et al. Development. 2013 Jan 1;140(1):117–25. PubMed Europe PMC Scholia
  8. SPCA2 regulates Orai1 trafficking and store independent Ca2+ entry in a model of lactation. Cross BM, Hack A, Reinhardt TA, Rao R. PLoS One. 2013 Jun 28;8(6):e67348. PubMed Europe PMC Scholia