title: Influence of terminal differentiation and PACAP on the cytokine, chemokine, and growth factor secretion of mammary epithelial cells.
abstract: Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide with trophic and cytoprotective effects, has been shown to affect cell survival, proliferation, and also differentiation of various cell types. The high PACAP level in the milk and its changes during lactation suggest a possible effect of PACAP on the differentiation of mammary epithelial cells. Mammary cell differentiation is regulated by hormones, growth factors, cytokines/chemokines, and angiogenic proteins. In this study, differentiation was hormonally induced by lactogenic hormones in confluent cultures of HC11 mouse mammary epithelial cells. We investigated the effect of PACAP on mammary cell differentiation as well as release of cytokines, chemokines, and growth factors. Differentiation was assessed by expression analysis of the milk protein β-casein. Differentiation significantly decreased the secretion of interferon gammainduced protein (IP)-10, "regulated upon activation normal T cell expressed and presumably secreted" (RANTES), insulin-like growth factor-binding protein (IGFBP)-3 and the epidermal growth factor receptor (EGFR) ligands, such as epidermal growth factor (EGF) and amphiregulin (AREG). The changes in the levels of IP-10 and RANTES may be relevant for the alterations in homing of T cells and B cells at different stages of mammary gland development, while the changes of the EGFR ligands may facilitate the switch from proliferative to lactating stage. PACAP did not modulate the expression of β-casein or the activity of hormone-induced pathways as determined by the analysis of phosphorylation of Akt, STAT5, and p38 MAPK. However, PACAP decreased the release of EGF and AREG from non-differentiated cells. This may influence the extracellular signal-related transactivation of EGFR in the non-differentiated mammary epithelium and is considered to have an impact on the modulation of oncogenic EGFR signaling in breast cancer.
authors: Department of Anatomy, PTE-MTA "Lendulet" PACAP Research Team, University of Pecs, Szigeti ut 12, Pecs, 7624, Hungary.
authors: Katalin
authors: K
authors: Csanaky
authors: Wolfgang
authors: W
authors: Doppler
authors: Andrea
authors: A
authors: Tamas
authors: Krisztina
authors: K
authors: Kovacs
authors: Gabor
authors: G
authors: Toth
authors: Dora
authors: D
authors: Reglodi
mesh_terms: D066258:Amphiregulin; D000818:Animals; D002364:Caseins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D002364:Caseins; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D018972:Insulin-Like Growth Factor Binding Protein 3; D036341:Intercellular Signaling Peptides and Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D050799:STAT5 Transcription Factor; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases