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Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice

Pascal, LE and Ai, J and Masoodi, KZ and Wang, Y and Wang, D and Eisermann, K and Rigatti, LH and O'Malley, KJ and Ma, HM and Wang, X and Dar, JA and Parwani, AV and Simons, BW and Ittman, MM and Li, L and Davies, BJ and Wang, Z (2013) Development of a reactive stroma associated with prostatic intraepithelial neoplasia in EAF2 deficient mice. PLoS ONE, 8 (11).

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Abstract

ELL-associated factor 2 (EAF2) is an androgen-responsive tumor suppressor frequently deleted in advanced prostate cancer that functions as a transcription elongation factor of RNA Pol II through interaction with the ELL family proteins. EAF2 knockout mice on a 129P2/OLA-C57BL/6J background developed late-onset lung adenocarcinoma, hepatocellular carcinoma, B-cell lymphoma and high-grade prostatic intraepithelial neoplasia. In order to further characterize the role of EAF2 in the development of prostatic defects, the effects of EAF2 loss were compared in different murine strains. In the current study, aged EAF2-/- mice on both the C57BL/6J and FVB/NJ backgrounds exhibited mPIN lesions as previously reported on a 129P2/OLA-C57BL/6J background. In contrast to the 129P2/OLA-C57BL/6J mixed genetic background, the mPIN lesions in C57BL/6J and FVB/NJ EAF2-/- mice were associated with stromal defects characteristic of a reactive stroma and a statistically significant increase in prostate microvessel density. Stromal inflammation and increased microvessel density was evident in EAF2-deficient mice on a pure C57BL/6J background at an early age and preceded the development of the histologic epithelial hyperplasia and neoplasia found in the prostates of older EAF2 -/- animals. Mice deficient in EAF2 had an increased recovery rate and a decreased overall response to the effects of androgen deprivation. EAF2 expression in human cancer was significantly down-regulated and microvessel density was significantly increased compared to matched normal prostate tissue; furthermore EAF2 expression was negatively correlated with microvessel density. These results suggest that the EAF2 knockout mouse on the C57BL/6J and FVB/NJ genetic backgrounds provides a model of PIN lesions associated with an altered prostate microvasculature and reactive stromal compartment corresponding to that reported in human prostate tumors. © 2013 Pascal et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pascal, LElep44@pitt.eduLEP44
Ai, J
Masoodi, KZ
Wang, Y
Wang, Ddaw112@pitt.eduDAW112
Eisermann, K
Rigatti, LHrigattil@pitt.eduRIGATTIL
O'Malley, KJ
Ma, HM
Wang, X
Dar, JA
Parwani, AV
Simons, BW
Ittman, MM
Li, L
Davies, BJbjd40@pitt.eduBJD40
Wang, Zwangz2@pitt.eduWANGZ2
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorFraidenraich, DiegoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 18 November 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 11
DOI or Unique Handle: 10.1371/journal.pone.0079542
Schools and Programs: School of Medicine > Pathology
School of Medicine > Urology
Refereed: Yes
Date Deposited: 30 Jan 2014 18:07
Last Modified: 02 Feb 2019 16:56
URI: http://d-scholarship.pitt.edu/id/eprint/20398

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