Forced activation of Stat5 subjects mammary epithelial cells to DNA damage and preferential induction of the cellular response mechanism during proliferation

• Published in: Journal of cellular physiology Vol. 226; no. 3; pp. 616 - 626
• Main Authors: Eilon, Tali, Barash, Itamar
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2011
• Subjects: Acetylcysteine - pharmacology; Animals; Cell Count; Cell Death - drug effects; Cell Line; Cell Proliferation - drug effects; DNA Damage; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Gene Expression Regulation, Neoplastic - drug effects; Histones - metabolism; Humans; Hydrocortisone - pharmacology; In Situ Nick-End Labeling; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Metabolic Networks and Pathways - drug effects; Metabolic Networks and Pathways - genetics; Mice; Mice, Transgenic; Prolactin - pharmacology; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Transfection
• ISSN: 0021-9541; 1097-4652; 1097-4652
• DOI: 10.1002/jcp.22381

Parity‐dependent adenocarcinoma tumors developed in postestropausal transgenic mice expressing a constitutively active Stat5 variant (STAT5ca) in their mammary gland. These tumors maintained elevated expression levels of genes regulating the cellular DNA damage response (DDR) mechanism, compared to the intact gland. No correlation with STAT5ca expression was observed for these genes in the established tumors. However, activated Stat5a in individual cells of the rarely and earlier developed hyperplasia was associated with induced Chk2 activity. Deregulated Stat5 may already cause DNA damage during the fertile period. This hypothesis and the specific vulnerable stage were further studied in mammary epithelial cells that were stably transfected with β‐lactoglobulin (BLG)/STAT5ca and exposed to a reproduced reproductive cycle. During the pregnancy‐like proliferative state, STAT5ca expression was induced by the added lactogenic hormones. Production of reactive oxygen species, rather than proliferation, served as the primary mediator of DNA damage and cellular DDR. Differentiated cells expressed higher levels of STAT5ca and retained the DNA nicks. However, the elevated expression of the genes involved in DDR was downregulated. Higher levels of DNA damage were also detected in the mammary gland of transgenic mice expressing the BLG/STAT5ca during pregnancy and lactation. However, the relative number of damaged cells was much lower than that in the reproduced in vitro stages and the insults were generally associated with apoptosis and DDR. This study implicates pregnancy as the vulnerable stage for deregulated Stat5 activity, and demonstrates that DNA insults in viable differentiated mammary epithelial cells are ignored by the DDR mechanism. J. Cell. Physiol. 226: 616–626, 2011. © 2010 Wiley‐Liss, Inc.