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Systems analysis of the prostate tumor suppressor NKX3.1 substantiates roles in DNA repair and a transcriptional program that drives luminal cell differentiation

ABSTRACT: NKX3.1 is an androgen-regulated, prostate-specific gene located on chromosome 8p21, a region frequently undergoing allelic loss in human prostate cancer. Mice deficient in NKX3.1 show signs of epithelial de-differentiation and develop dysplasia and prostatic intraepithelial neoplasia (PIN) that progresses to overt prostate cancer when combined with deletions of additional tumor suppressors such as PTEN or p27Kip1. Although NKX3.1 displays the typical features of an NK class homeobox transcription factor, mechanisms of NKX3.1-mediated tumor suppression remain insufficiently understood because neither the transcriptional program governed by NKX3.1 nor its interacting proteins have been comprehensively revealed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE47030 | GEO | 2013/12/25

SECONDARY ACCESSION(S): PRJNA205049

REPOSITORIES: GEO

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Project description:In our investigations of the molecular pathways of prostate tumorigenesis in Nkx3.1; Pten mutant mice using gene expression profiling, we now find that the AP-1 transcription factors, c-Jun and c-Fos, are significantly up-regulated during cancer progression. Forced expression of c-Fos and c-Jun in prostate cancer cells results in increased tumorigenicity, activation of Erk MAP kinase, and enhanced survival in the absence of androgens, which are hallmarks of disease progression. In humans, Jun and Fos proteins are significantly up-regulated during prostate cancer progression and significantly correlated with activation of Erk MAP kinase. Most notably, expression of Jun is associated with disease recurrence independent of other currently used prognostic indicators. These analyses reveal a hitherto unappreciated role for AP-1 transcription factors in prostate cancer progression vis-Ã -vis Erk MAP kinase signaling, as well as the identification of a novel marker of disease recurrence, namely c-Jun. Experiment Overall Design: Mouse prostate was collected from wild-type or the Nkx3.1; Pten compound mutant mice at the age of 8-16 months. One lobe of dosolateral prostate was snap-frozen in OCT and stored at -80ÂºC for laser capture microdissection (LCM). To obtain androgen-independent lesions, mice were castrated at 7 to 14 months of age. Mice were sacrificed for analysis at 8 to 16 months of age and one dosolateral prostatic lobe was snap-frozen in OCT and stored at -80ÂºC for LCM. Approximate 1000 Prostate epithelial cells were isolated from normal prostate, dysplasia, prostatic intraepithelial neoplasia (PIN) or cancer lesions using PixCell IIE LCM system (Arcturus), followed by RNA linear amplification and labeling using Small Sample Labeling Protocol VII (Affymetrix). Samples were labeled using a BioArray High Yield RNA transcript labeling kit (Enzo Life Scientific) and were hybridized to MOE430A GeneChips containing 22,690 well characterized mouse genes/ESTs (Affymetrix).

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Systems analysis of the prostate tumor suppressor NKX3.1 substantiates roles in DNA repair and a transcriptional program that drives luminal cell differentiation

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