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 [http://www.ncbi.nlm.nih.gov/pubmed/16231422 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) [http://www.ncbi.nlm.nih.gov/pubmed/16231422 1]. CEBPA and CEBPB are related to the balance between proliferation and differentiation of epithelial cells [http://www.ncbi.nlm.nih.gov/pubmed/9513715 2]. The TNFSF11/ TNFRSF11A pathway is associated with proliferation [http://www.ncbi.nlm.nih.gov/pubmed/16231422 1]. MYC, galanin and PTPN1 are regulators of the JAK2/STAT5 pathway and UFS are implicated in cell cycle control [http://www.ncbi.nlm.nih.gov/pubmed/16231422 1] [http://www.ncbi.nlm.nih.gov/pubmed/15689376 3] [http://www.ncbi.nlm.nih.gov/pubmed/12907752 4] [http://www.ncbi.nlm.nih.gov/pubmed/23154416 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 [http://www.ncbi.nlm.nih.gov/pubmed/16231422 1]. ERBB4 substitutes JAK2 by phosphorylating STAT5.
Finally, in the last two cases, estrogen binds to its receptors, ESR1 and ESR2, and stimulates PGR [http://www.ncbi.nlm.nih.gov/pubmed/16231422 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 [http://www.ncbi.nlm.nih.gov/pubmed/22917536 6].
PNCK appears to negatively regulate EGFR and MAPK signaling during pregnancy [http://www.ncbi.nlm.nih.gov/pubmed/18562482 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 [http://www.ncbi.nlm.nih.gov/pubmed/23840669 8].ef8ef8cc6ef8b8fe31afdb8fef8bfcef8e31ef8e04ef8ef8bfccc6ef8bfcdd2ef8cc6bfcef8ef8ef8ef8ef8ef8Type your comment hereef8ef8cc6cc6ef8cc6ef8ef8ef8ef8e04cc6ef8ef8ef8afdef8ef8ef8ef8cc622917536PubMedThe 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.Biochem Biophys Res Commun2012Shrestha SCao SLin VCmilk secreting cellCL:0000314Cell Type12907752PubMedDiminished 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.Mol Endocrinol2003Hadsell DLBonnette SGeorge JTorres DKlimentidis YGao SHaney PMSummy-Long JSoloff MSParlow AFSirito MSawadogo M15689376PubMedDevelopmental stage determines the effects of MYC in the mammary epithelium.Development2005Blakely CMSintasath LD'Cruz CMHahn KTDugan KDBelka GKChodosh LA23154416PubMedProtein tyrosine phosphatase 1B restrains mammary alveologenesis and secretory differentiation.Development2013Milani ESBrinkhaus HDueggeli RKlebba IMueller UStadler MKohler HSmalley MJBentires-Alj M9513715PubMedComposite response elements mediate hormonal and developmental regulation of milk protein gene expression.Biochem Soc Symp1998Rosen JMZahnow CKazansky ARaught B18562482PubMedPregnancy-upregulated nonubiquitous calmodulin kinase induces ligand-independent EGFR degradation.Am J Physiol Cell Physiol2008Deb TBCoticchia CMBarndt RZuo HDickson RBJohnson MD16231422PubMedInformation networks in the mammary gland.Nat Rev Mol Cell Biol2005Hennighausen LRobinson GW23840669PubMedSPCA2 regulates Orai1 trafficking and store independent Ca2+ entry in a model of lactation.PLoS One2013Cross BMHack AReinhardt TARao Rregulatory pathwayPW:0000004Pathway Ontology