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Nuclear Factor-B Is Constitutively Activated in Prostate Cancer In vitro and Is Overexpressed in Prostatic Intraepithelial Neoplasia and Adenocarcinoma of the Prostate

Departments of ¹ Medicine, ² Biostatistics, ³ Urology, ⁴ Microbiology and Immunology, ⁵ Pathology, and ⁶ Surgery, Indiana University, Indianapolis, Indiana; ⁷ Department of Pathology, Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; and ⁸ Walther Cancer Institute, Indianapolis, Indiana

Purpose: The transcription factor nuclear factor-B (NF-B) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis.

Experimental Design: Electromobility gel shift assays were used to evaluate NF-B DNA binding in vitro. The functional relevance of NF-B DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-B inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-B subunit was used to determine the frequency and location of NF-B in 97 prostatectomy specimens. The amount of staining was quantified on a 0–3+ scale.

Results: An electromobility gel shift assay confirmed the presence of NFB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-B and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage.

Conclusions: NF-B is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-B, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-B for the prevention and/or treatment of prostate cancer.

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