title: TGF-beta promotes cell death and suppresses lactation during the second stage of mammary involution.
abstract: Transforming growth factor beta (TGF-beta) ligands are known to regulate virgin mammary development and contribute to initiation of post-lactation involution. However, the role for TGF-beta during the second phase of mammary involution has not been addressed. Previously, we have used an MMTV-Cre transgene to delete exon 2 from the Tgfbr2 gene in mammary epithelium, however we observed a gradual loss of T beta RII deficient epithelial cells that precluded an accurate study of the role for TGF-beta signaling during involution timepoints. Therefore, in order to determine the role for TGF-beta during the second phase of mammary involution we have now targeted T beta RII ablation within mammary epithelium using the WAP-Cre transgene [T beta RII(WKO)Rosa26R]. Our results demonstrated that TGF-beta regulates commitment to cell death during the second phase of mammary involution. Importantly, at day 3 of mammary involution the Na-Pi type IIb co-transporter (Npt2b), a selective marker for active lactation in luminal lobular alveolar epithelium, was completely silenced in the WAP-Cre control and T beta RII(WKO)Rosa26R tissues. However, by day 7 of involution the T beta RII(WKO)Rosa26R tissues had distended lobular alveoli and regained a robust Npt2b signal that was detected at the apical luminal surface. The Npt2b abundance and localization positively correlated with elevated WAP mRNA expression, suggesting that the distended alveoli were the result of an active lactation program rather than residual milk protein and lipid accumulation. In summary, the results suggest that an epithelial cell response to TGF-beta signaling regulates commitment to cell death and suppression of lactation during the second phase of mammary involution.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Bierie
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Stover
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002470:Cell Survival; D005260:Female; D020287:In Situ Nick-End Labeling; D007774:Lactation / Q000502:physiology*; D050356:Lipid Metabolism; D008321:Mammary Glands, Animal / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D008894:Milk Proteins; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C024471:whey acidic proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077294:Receptor, Transforming Growth Factor-beta Type II