Dysregulation of mammary Stats 1,3 and 5 and PRL receptors by overexpression of TGFalpha.
Mammary TGFalpha overexpression results in delayed involution and eventually mammary cancer in transgenic mice. We hypothesized that STATs and PRL receptors (PRLR), critical regulators of mammary function, are altered in these animals and may contribute to this phenotype. We examined these factors late in the first pregnancy (d.18) and during normal involution (d.4 post-lactation) in WAP-TGFalpha transgenic mice and non-transgenic controls. Long form PRLR mRNA in WAP-TGFalpha glands at both pregnant d.18 and d.4 post-lactation was significantly reduced compared to controls, and PRLR-S3 failed to rise during involution. Total and pTyr STAT 1,3,5a and 5b also were altered. STAT 3 was higher at both times in WAP-TGFalpha glands. STAT 5a and 5b were lower at late pregnancy, but higher post-lactation; however, pTyr(694) STAT 5 was abnormally low at both times. Thus overexpression of TGFalpha has direct or indirect effects on both STATs and PRL responsiveness in vivo, which may reflect mechanisms of TGFalpha-induced mammary epithelial abnormalities.
Schroeder
M D
MD
Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive West, Madison, WI 53706, USA.
Rose-Hellekant
T A
TA
Sandgren
E P
EP
Schuler
L A
LA
D000818:Animals; D001940:Breast / Q000737:chemistry / Q000254:growth & development / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins; D010766:Phosphorylation; D011247:Pregnancy; D011388:Prolactin / Q000235:genetics; D020033:Protein Isoforms / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011981:Receptors, Prolactin / Q000187:drug effects* / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011981:Receptors, Prolactin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D011388:Prolactin