RGD Reference Report - The E2F1/DNMT1 axis is associated with the development of AR negative castration resistant prostate cancer. - Rat Genome Database

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The E2F1/DNMT1 axis is associated with the development of AR negative castration resistant prostate cancer.

Authors: Valdez, CD  Kunju, L  Daignault, S  Wojno, KJ  Day, ML 
Citation: Valdez CD, etal., Prostate. 2013 Dec;73(16):1776-85. doi: 10.1002/pros.22715. Epub 2013 Sep 4.
RGD ID: 9588628
Pubmed: PMID:24038143   (View Abstract at PubMed)
DOI: DOI:10.1002/pros.22715   (Journal Full-text)

BACKGROUND: Research on castration resistant prostate cancer (CRPC) has focused primarily on functional alterations of the androgen receptor (AR). However, little is known about the loss of AR gene expression itself and the possible contribution of AR negative cells to CRPC. METHODS: Human and murine prostate cancer tissue microarrays (TMAs) were evaluated with antibodies specific for E2F1, DNA methyltransferase 1 or AR. The human prostate cancer TMA consisted of clinical samples ranging from normal tissue to samples of metastatic disease. The murine TMA was comprised of benign, localized or metastatic prostate cancer acquired from TRAMP mice treated with castration and/or 5'-Aza-2'-deoxycytidine (5Aza). RESULTS: Immunohistochemical analysis revealed increased nuclear DNMT1 staining in localized PCa (P < 0.0001) and metastatic PCa (P < 0.0001) compared to normal tissue. Examination of specific diagnoses revealed that Gleason seven tumors exhibited greater nuclear DNMT1 staining than Gleason six tumors (P < 0.05) and that metastatic tissue exhibited greater levels of nuclear DNMT1 than Gleason seven tumors (P < 0.01). Evaluation of the murine tissue cores revealed that 8.2% and 8.1% of benign tissue cores stained positive for E2F1 and DNMT1 respectively, while 97.0% were AR positive. Conversely, 81% and 100% of tumors were positive for E2F1 and DNMT1 respectively. This was in stark contrast to only 18% of tumors positive for AR. Treatment of mice with 5Aza reduced DNMT1 staining by 30%, while AR increased by 27%. CONCLUSIONS: These findings demonstrate that the E2F1/DNMT1 inhibitory axis of AR transcription is activated during the emergence of CRPC.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DNMT1Humanprostate cancer disease_progressionIEP protein:increased expression:nucleus:RGD 
Dnmt1Ratprostate cancer disease_progressionISODNMT1 (Homo sapiens)protein:increased expression:nucleus:RGD 
Dnmt1Mouseprostate cancer disease_progressionISODNMT1 (Homo sapiens)protein:increased expression:nucleus:RGD 
DNMT1HumanProstatic Neoplasms treatmentISODnmt1 (Mus musculus) RGD 
Dnmt1RatProstatic Neoplasms treatmentISODnmt1 (Mus musculus) RGD 
Dnmt1MouseProstatic Neoplasms treatmentIEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dnmt1  (DNA methyltransferase 1)

Genes (Mus musculus)
Dnmt1  (DNA methyltransferase 1)

Genes (Homo sapiens)
DNMT1  (DNA methyltransferase 1)


Additional Information