Tumors caused by overexpression and forced activation of Stat5 in mammary epithelial cells of transgenic mice are parity-dependent and developed in aged, postestropausal females.
In transgenic mice overexpressing Stat5 or a constitutively activated Stat5 variant (STAT5ca), we show for the first time that parity is required for the development of tumors in postestropausal females. Tumors were detected in glands of multiparous transgenic female mice after latency period of 14 months, but rarely in their age-matched virgin (AMV) counterparts. This period was not affected by distinguishable tumor pathologies and was not dependent upon transgenic Stat5 variant. To associate Stat5 deregulation, parity and the postestropausal tumor occurrence with mammary cancer formation, the activities of endogenous and transgenic Stat5 were measured in the glands of aged multiparous and AMV females. No differences in phosphorylated Stat5 (pStat5) levels were found between the 2 cohorts. However, promoter sequences comprising the Stat5 binding sites from the cyclin D1 or the bcl-x genes associate differentially with acetylated histone H4 in aged multiparous and AMV STAT5ca transgenic females. Individual epithelial cells varied greatly with respect to the presence of nuclear pStat5. A small subset of epithelial cells, in which pStat5 and cyclin D1 were co-expressed, was exclusively present in the multiparous glands. Changes in chromatin structure might persist past the reproductive life time of the multiparous mice and contribute to the transcription of the cyclin D1 gene by activated Stat5. This may cause the detectable expression of cyclin D1 and add to the process of tumorigenesis.
Eilon
Tali
T
Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, Israel.
Groner
Bernd
B
Georg Speyer Haus, Institute for Biomedical Research, Frankfurt/M, Germany.
Barash
Itamar
I
Institute of Animal Science, ARO, The Volcani Center, Bet-Dagan, Israel.
D000375:Aging / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D004847:Epithelial Cells; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D017698:Postmenopause / Q000502:physiology*; D011485:Protein Binding; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D006657:Histones; D050799:STAT5 Transcription Factor; D019938:Cyclin D1