Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits wnt-1-induced mammary tumorigenesis.
The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads to mammary hyperplasia and subsequently focal mammary tumors. To explore the possibility that PTEN intersects with Wnt-induced tumorigenesis, mice that ectopically express PTEN and Wnt-1 in mammary epithelium were generated. PTEN overexpression resulted in an 11% reduction of Wnt-1-induced tumors within a 12-month period and the onset of tumors was delayed from an average of 5.9 to 7.7 months. The rate of tumor growth, measured from 0.5 cm diameter until the tumors reached 1.0 cm diameter, was increased from 8.4 days in Wnt-1 mice to 17.7 days in Wnt-1 mice overexpressing PTEN. Here we show for the first time in vivo that overexpression of PTEN in the Wnt-1 transgenic mice resulted in a marked decrease in the insulin-like growth factor (IGF)-I receptor levels leading to a reduced IGF-I-mediated mitogenesis. Moreover, the percentage of BrdUrd-positive epithelial nuclei was decreased by 48%. beta-Catenin immunoreactivity was significantly decreased and the percentage of signal transducer and activator of transcription 5a (stat5a)-positive mammary epithelial cells was increased by 2-fold in Wnt-1 mice overexpressing PTEN. The present study shows that PTEN can partially inhibit the Wnt-1-induced mammary tumorigenesis in early neoplastic stages by blocking the AKT pathway and by reducing the IGF-I receptor levels in mammary gland. This study identifies the PTEN as a therapeutic target for the treatment of mammary cancer and presumably other types of cancer.
Zhao
Hong
H
Diabetes Branch and Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-1758, USA.
Cui
Yongzhi
Y
Dupont
Joelle
J
Sun
Hui
H
Hennighausen
Lothar
L
Yakar
Shoshana
S
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism; D019076:Transgenes; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin; D019938:Cyclin D1; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020780:Matrix Metalloproteinase 9