Twist is up-regulated in response to Wnt1 and inhibits mouse mammary cell differentiation.
Wnt1, initially identified as a mammary oncogene, can activate transcription via beta-catenin/TCF complexes. Twist, a transcription factor of the basic helix-loop-helix class, has also been suggested to have oncogenic properties. The aim of this study was to determine whether Twist is regulated by Wnt1 and might thus be a novel mediator of Wnt signaling. We found that Twist was up-regulated in C57MG and HC11 murine mammary epithelial cells in response to Wnt1 expression. Additionally, we detected Twist expression in normal mammary gland and found elevated Twist expression in approximately 70% of mammary tumors from Wnt1 transgenic mice. A murine Twist promoter fragment was shown to be responsive to beta-catenin, and its activity was enhanced by coexpression of c-jun and Ets factors of the PEA3 family. Both PEA3 factors and c-jun were highly expressed in tumors from Wnt1 transgenic mice and may therefore contribute to the increased Twist expression observed in these tumors. To evaluate functional consequences of Twist induction, we examined the effect of Twist on mammary cell differentiation. Strikingly, overexpression of either Wnt1 or Twist in HC11 mammary epithelial cells completely suppressed induction of the milk protein beta-casein in response to lactogenic hormones. Additionally, Wnt1, but not Twist, partially abrogated induction of WDNM1, another marker of lactogenic differentiation. Taken together, our data indicate that Twist expression is regulated by Wnt/beta-catenin signaling and that both Wnt1 and Twist can function as inhibitors of lactogenic differentiation, an effect that could contribute to mammary tumorigenesis.
Howe
Louise R
LR
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York 10021, USA. lrhowe@med.cornell.edu
Watanabe
Osamu
O
Leonard
James
J
Brown
Anthony M C
AM
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D051879:Twist-Related Protein 1; D015854:Up-Regulation; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D051176:beta Catenin; C065788:transcription factor PEA3