title: MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells.
abstract: Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina-features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These "Super-Lo-MYC" mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a "paradoxical" increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Iwata
authors.forename: Denise
authors.initials: D
authors.lastname: Schultz
authors.forename: Jessica
authors.initials: J
authors.lastname: Hicks
authors.forename: Gretchen K
authors.initials: GK
authors.lastname: Hubbard
authors.forename: Laura N
authors.initials: LN
authors.lastname: Mutton
authors.forename: Tamara L
authors.initials: TL
authors.lastname: Lotan
authors.forename: Carlise
authors.initials: C
authors.lastname: Bethel
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Lotz
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.forename: William G
authors.initials: WG
authors.lastname: Nelson
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: MengMeng
authors.initials: M
authors.lastname: Xu
authors.forename: Uzoma
authors.initials: U
authors.lastname: Anele
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Koh
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Bieberich
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000737:chemistry* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors