Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer.

The DNA base excision repair pathway is responsible for the repair of cellular alkylation and oxidative DNA damage. A crucial step in the BER pathway involves the cleavage of baseless sites in DNA by an apurinic/apyrimidinic or baseless (AP) endonuclease (Ape1/ref-1), which is a multifunctional enzyme that acts not only as an AP endonuclease but also as a redox-modifying factor for a variety of transcription factors including Fos, Jun, paired box containing genes (PAX), nuclear factor-kappaB, hypoxia-inducible factor alpha (HIF-1alpha), HIF-like factor (HLF), p53, and others. The expression of Ape1/ref-1 in prostate has not been characterized previously. Ape1/ref-1 nuclear immunohistochemistry levels, scored for intensity as 1+, 2+, or 3+, were 91, 3, and 6% in benign hypertrophy (BPH), 0, 42, and 58% in prostatic intraepithelial neoplasia (PIN) and 3, 30, and 67% in prostate cancer, respectively, clearly showing an increase in Ape1/ref-1 nuclear staining in the PIN and cancer compared with BPH. Furthermore, the level of cytoplasmic staining of Ape1/ref-1 in cancer and PIN were elevated (42 and 36%, respectively) compared with BPH (5%). There was no correlation with prostate-specific antigen values or doubling times to Ape1/ref-1 levels. In conclusion, we have demonstrated that Ape1/ref-1 is dramatically elevated in prostate cancer, the level of staining of Ape1/ref-1 increases from low in BPH to intense in PIN and cancer, and there is an increase in the amount of Ape1/ref-1 in the cytoplasm of PIN and cancer compared with BPH. Given these results, we conclude that Ape1/ref-1 may be a diagnostic marker for early prostate cancer and play a role, through its repair, redox, or both functions, in the physiology of the early development of prostate cancer.

Gynandroblastoma with elements resembling juvenile granulosa cell tumor.

Gynandroblastoma is an extremely rare sex cord-stromal tumor that exhibits significant ovarian and testicular differentiation. In most previously reported tumors, adult granulosa cell tumor has formed the ovarian-type component and Sertoli or Sertoli-Leydig cell tumor (SLCT) has formed the testicular-type component. In contrast, the ovarian-type element in the case reported here resembled juvenile granulosa cell tumor (JGCT). The testicular-type elements accounted for 20% of the tumor and resembled intermediate-grade SLCT. The Sertoli cells had strong cytoplasmic staining for cytokeratin CAM 5.2 and positive nuclear staining with estrogen and progesterone receptor, whereas the JGCT-like areas were negative for these antibodies. Ultrastructurally, the JGCT-like areas consisted of groups of cells that were invested by a basal lamina and had low nuclear-cytoplasmic ratios, cytoplasmic lipid droplets, and simple junctional complexes. The Sertoli cells in the SLCT-like areas had long, tight junctions and well-formed desmosomes. Gynandroblastoma usually presents clinically as an abdominal mass, often associated with either virilizing or feminizing manifestations. The prognosis is favorable and similar to that of the individual tumor components, but clinical follow-up in the small number of cases has been limited.

The apurinic/apyrimidinic endonuclease (APE/ref-1) DNA repair enzyme is elevated in premalignant and malignant cervical cancer.

The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) is responsible for the repair of AP sites in DNA. In addition, this enzyme has been shown to function as a redox factor facilitating the DNA-binding capability of JUN and FOS, HeLa AP-1, and numerous other transcription factors, including Myb, members of the CREB family and nuclear factor-kappa B. Although previously presumed to be ubiquitously expressed at comparable levels in all tissues and cell types, recent evidence has shown APE to vary significantly in its expression between tissues and even within tissues. To further characterize APE expression at various stages of cervical neoplasia, we investigated the levels of APE protein expression using immunohistochemistry in normal cervix, pre-invasive and invasive squamous lesions of the cervix, as well as in cervical cancer cell lines. We report here that the APE protein is predominantly expressed in the nuclei of cells from both primary tumors and cervical cell lines, but the level of APE protein is significantly and dramatically elevated in cervical cancer tissue. These results implicate the use of anti-APE antibodies as an effective reagent in the early detection of premalignant and malignant cancer of the cervix. These findings are suggestive that the increase of a DNA repair enzyme in cancerous cells may allow these cells to be refractive to chemotherapy.

Sigmoid colon carcinoma metastatic to prostate.

Although primary prostatic carcinoma is very common, prostatic metastasis is unusual. We describe a unique example of prostatic metastasis from noncontiguous colon cancer, after presumed curative resection of the primary tumor. Potential mechanisms of metastasis are examined in the context of clinical and histopathologic evidence. A possible role is proposed for early transrectal ultrasound examination in diagnosis of patients with unexplained urologic symptoms after resection of colorectal cancer.