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PubMed1988

Phagocytic and natural killer cytotoxic responses of murine transitional cell carcinoma to postsurgical immunochemotherapy.

Postsurgical immunochemotherapy with Corynebacterium parvum (CP) and cis-diamminedichloroplatinum (II) (CDDP) was evaluated in mice with transitional cell carcinoma (MBT-2). C3H/He mice were transplanted subcutaneously in the hind limb with 5 x 10(5) tumor cells. Ten to 14 days later when the tumor reached a diameter of five to seven mm., it was surgically removed. Mice were then randomized into four groups to receive a total of three treatments on days 1, 3 and 5 after surgery: 1) saline (control group); 2) CP, 250 micrograms. into the surgical site; 3) CDDP, 5 micrograms./gm. body weight intraperitoneally; and 4) combined CP and CDDP. Recurrence of tumor occurred in 70%, 52%, 55% and 28% of mice receiving surgery only, CP, CDDP, and combined CP and CDDP respectively. In the second part of the experiment, phagocytic activity using chemiluminescence assay and natural killer (NK) activity using chromium-51 release assay were determined with cells from the peritoneum, spleen and inguinal lymph nodes. CP or CDDP alone enhanced the phagocytic and NK activity. The most significant enhancement was obtained with cells from the inguinal lymph nodes of mice receiving combined CP and CDDP, the group with the lowest tumor recurrence. These results suggest that combination of CP and CDDP may be useful in control of postsurgical recurrence of bladder cancer.

Animals↗
PubMedDate not supplied

MCA performance in preoperative breast cancer patients.

Mucin-like carcinoma-associated antigen (MCA) is a new tumor associated antigen expressed on breast cancer cells independent of histological type and recognized by a two-site sandwich EIA (Roche) using the Mab b-12 as capture and detection antibody and a MCA cut-off of 11 U/ml. MCA serum levels were determined in 409 breast cancer patients and in 100 pts with benign breast disease histologically confirmed and staged according to UICC. The sensitivity of MCA regarding the stage of disease was elevated only in metastatic patients (89%) and the MCA values of this group were significantly different compared to those of patients with early or locally advanced breast cancer. In the group of benign patients, the specificity was 81%. The correlation between MCA values and number of involved axillary lymph nodes showed significant differences in the O versus 4-10 node subgroup (p < 0.001), in O versus > 10 and in 1-3 versus 4-10 node subgroup (p < 0.05); elevated MCA sensitivity was found in the 4-10 and > 10 subgroups. In our experience, the determination of MCA is not useful for early diagnosis of breast cancer nor does it indicate the extent of lymph node involvement. With regard to the prediction of tumor recurrence in postoperative patients free of disease, MCA levels increased concomitantly with the clinical evidence of relapse. These findings suggest that the MCA assay is highly sensitive only in patients with metastatic breast cancer; therefore one of the most promising test application seems to be for monitoring the clinical course of advanced disease patients.

Adult↗
PubMed2000

Molecular diagnosis of head and neck cancer.

Patients with advanced stages of head and neck cancer frequently develop locoregional recurrence as well as distant metastases. These data indicate that traditional diagnostic methods such as histopathology and radiology are not sensitive enough to detect the small numbers of tumor cells which are left behind, defined as minimal residual disease (MRD). Sensitive diagnostic assays based on molecular markers appear to be powerful tools to improve the staging of these patients. At the DNA level, tumor-specific p53 mutations seem to have great potential for the detection of "occult" tumor cells at surgical margins and lymph nodes. At the RNA level HNSCC associated antigens like the E48 antigen, allow the detection of rare HNSCC cells in blood and bone marrow and, it is hoped, also in lymph nodes and lymph node aspirates. However, the molecular assays which are used to detect MRD are subject to certain (technical) problems which affect their sensitivity and specificity. In this paper we will present examples of molecular assays such as the plaque assay using p53 mutations and the E48 RT-PCR, and show their use for MRD detection in cervical lymph nodes. In addition, we will discuss the problems and pitfalls associated with these sensitive techniques.

Artifacts↗
PubMed1996

123I-vasoactive intestinal peptide (VIP) receptor scanning: update of imaging results in patients with adenocarcinomas and endocrine tumors of the gastrointestinal tract.

Recent data suggest that functional receptors (R) for vasoactive intestinal peptide (VIP) are expressed on various tumor cells. The high-level expression of VIPR on tumor cells provided the basis for the successful use of 123I-labeled VIP for the in vivo localization of intestinal adenocarcinomas and endocrine tumors. We here report an update of our imaging results using 123I-VIP (150-200 MBg/1 microgram/patient) in 169 patients. In patients with pancreatic adenocarcinomas without liver metastases, the primary/recurrent tumor was visualized in 16 of 18 patients (89%) and liver metastases were imaged in 15 of 16 patients. In 11 of 12 patients with colorectal adenocarcinomas, the primary/recurrent tumor (92%) was imaged by 123I-VIP. Also, in 21 of 25 patients, liver metastases (84%); in 3 of 6 patients, lung metastases (50%); and in 4 of 5 patients, lymph-node metastases (80%) were imaged by 123I-VIP. In 10 of 10 patients with gastric adenocarcinomas, the primary/recurrent tumor; in 3 of 4 patients, liver metastases; and in 2 of 2 patients, lymph-node metastases were visualized by 123I-VIP. 123I-VIP localized primary intestinal carcinoid tumors in 15 of 17 patients (88%) and 8 of 10 primary insulinomas (80%). We conclude that the 123I-VIPR scintigraphy localizes intestinal adenocarcinomas and endocrine tumors as well as metastatic tumor sites.

Adenocarcinoma↗
PubMed2005

Carcinoma cell-specific Mig-7: a new potential marker for circulating and migrating cancer cells.

Identification of genes that are expressed in a cancer cell-specific manner can provide markers for detection, diagnosis, and disease progression. We have previously reported that receptor tyrosine kinase ligands in concert with ligation of alphavbeta5 integrin induce expression of Mig-7 restricted to carcinoma cells. Because of this highly specific expression, we hypothesized that Mig-7 could be used as a marker of occult tumor cells. The objective of this study was to begin to test this hypothesis by generating Mig-7 specific antisera and RT-PCR methods for detection of Mig-7 expression in tissues and blood from cancer patients as compared to those from normal subjects. By immunohistochemistry and by RT-PCR, we detected Mig-7 mRNA in lymph nodes from 7 out of 9 (77.8%) endometrial carcinoma xenograft mice but not from any of the 5 negative control animals. Mig-7 expression was more specific than Met expression, the RTK that binds Scatter factor and is used as a marker of poor progression, in endometrial carcinoma as compared to normal endometrial tissue samples. In 87.3% of tumors from various tissues including breast, lung, colon and ovary, we detected Mig-7 expression. Blood samples from untreated metastatic cancer patients also displayed Mig-7 mRNA in contrast to a lack of expression in chemotherapy treated or normal individuals. In conclusion, we report the first immunohistochemical and RT-PCR assays for Mig-7 and discuss its highly specific localization to cancer cells in contrast to an absence in normal cells. Our preliminary data indicate that Mig-7 may be a potential early marker of migrating and circulating carcinoma cells.

Animals↗
PubMed2004

Expression of serotonin receptors and role of serotonin in human prostate cancer tissue and cell lines.

BACKGROUND: Increase in the number of serotonin (5-HT) releasing neuroendocrine (NE) cells has been shown to be correlated with tumor progression, loss of androgen dependence, and poor prognosis. Serotonin is a well-known mitogen which mediates a wide variety of physiological effects via multiple receptors, of which receptor subtype 1 (5-HTR1) has been identified in prostate cancer (PC) cell lines. Recently, 5-HT has been found to show growth-promoting activity and to be functionally related to oncogenes. MATERIALS AND METHODS: Localization, protein content, and mRNA expression of 5-HTR subtype 1A, 1B, and 1D was studied in prostatic tissue (35 patients), metastases, PC cell lines, a benign prostatic stromal cell line (human prostate cell preparation (hPCP)), and xenografts of PC-3 cells by immunohistochemistry (IHC), Western blotting, and RT-PCR, respectively. The growth-inhibition effect of a 5-HT1A antagonist (NAN-190) on PC cell lines was studied using a bromodeoxyuridine (BrdU) assay. RESULTS: A strong immunoreaction of 5-HTR1A and 1B was demonstrated in high-grade tumor cells (35/35) and a small number of BPH cells, whereas 5-HTR1D was confined to vascular endothelial cells. 5-HTR1A was also demonstrated in PC cells metastasized to lymph node and bone, PC-3, DU145, LNCaP, and in xenografts of PC-3 cells and hPCP. Western blot analysis gave strong bands from PC tissue extracts compared to BPH tissue. Using RT-PCR, 5-HTR1A mRNA was demonstrated in all PC cell lines. An antagonist of 5-HTR1A (NAN-190) inhibited the growth of PC-3, DU145, and LNCaP cells but not of hPCP cells. CONCLUSIONS: This is the first study demonstrating an overexpression of 5-HTR subtypes 1A and 1B in PC cells, especially in high-grade tumors. Moreover, 5-HT stimulates proliferation of PC cells and 5-HTR1A antagonists inhibit proliferation. Thus, we propose that 5-HT has an important role in tumor progression, especially in the androgen-independent state of the disease. The design of specific antagonists for this type of receptor might be useful for the growth control of androgen-independent tumors.

Blotting, Western↗
PubMed1988

Coamplification of the hst-1 and int-2 genes in human cancers.

The hst-1 gene, previously designated the hst gene, was identified as a transforming gene by transfection assays of genomic DNAs from various types of human cancers. We analyzed for alterations of the hst-1 gene in 18 bladder cancers, 23 renal cell carcinomas and 5 esophageal cancers. Although rearrangement of the gene was not detected in any of these samples, amplification of the hst-1 gene was found in 4 samples of tumors, including an invasive bladder cancer, both primary esophageal cancer and its lymph node metastasis, and kidney metastasis of an esophageal cancer. The same degree of amplification of the int-2 gene, the product of which has significant homology with the hst-1-encoded protein, was also observed in all of these DNA samples with amplified hst-1 gene. This result indicates close chromosomal localization of the two genes, which were amplified as one amplification unit.

Cell Line↗
PubMed2003

Anti-cancer effect of genistein in oral squamous cell carcinoma with respect to angiogenesis and in vitro invasion.

Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers. OSCC generally has a poor prognosis due to its tendency towards local invasion and subsequent metastasis, which is mediated by multiple proteolytic enzymes and angiogenesis. The purpose of this study was to evaluate the anti-cancer effects of genistein, a soybean product known to be an effective natural anti-angiogenic agent, with respect to tumor growth, angiogenesis and in vitro invasion in an OSCC model. Northern blot analysis for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metalloproteinase-2 (MMP-2), in vitro invasion assay and gelatin zymography were carried out for HSC-3 cells treated with genistein (27.3 microg/ml). In the animal experiment, genistein (0.5 mg/kg) was injected into tumor (HSC-3)-bearing mice (male balb/c/nu). The tumor growth rate and metastasis to lymph node or lung were compared and the microvessel density (CD31) was subsequently analyzed by immunohistochemistry. The genistein-treated group showed a down-regulation in VEGF mRNA expression, but not in bFGF and MMP-2 mRNA expression. Genistein reduced in vitro invasion through the artificial basement membrane and gelatin zymography also showed a reduced gelatinolytic activity in the genistein-treated group. In the genistein-treated mice, a significantly lower CD31 immunoreactivity was found. However, the tumor growth and metastatic behavior in the experimental group and the control group were similar and there were no significant differences. These results suggest the possible use of genistein as an anti-cancer agent in oral squamous cell carcinoma. However, it appears from the present study that anti-angiogenic therapy consisting of a single application of genistein may not provide a satisfactory treatment for OSCC. As a result, further research is recommended to confirm that genistein may be employed as an adjunct treatment modality for OSCC.

Angiogenesis Inhibitors↗
PubMed1992

[Lymphokine-activated killer (LAK) therapy for advanced renal cell carcinoma: clinical study on arterial LAK therapy and experimental study on LAK cell activity].

Experimental and clinical studies were conducted on lymphokine-activated killer (LAK) cell therapy for advanced renal cell carcinoma (RCC). The traffic assay using radiolabeled LAK cells indicated short-term but appreciable accumulation of LAK cells in the tumor site when trans-arterially infused. By contrast, systemically infused LAK cells were localized not to the tumor tissue but to the lung. Therefore, we began treatment of the patients with extrapulmonary metastases by means of regional arterial administration of LAK cells and those who had pulmonary metastases by a systemic LAK therapy. Regimen of Interleukin-2 (IL-2) administration was bolus infusion of 5 x 10 U IL-2 twice daily. Frequency of LAK cell administration varied from one to three times a week depending upon the patient's condition. Eight out of 16 metastases, such as bone, muscle, and lymph node metastases, in 9 patients treated by arterial LAK therapy showed regression. Side effects during LAK therapy were not serious. Past history of having chemotherapy was an unfavorable factor that could reduce the sensitivity to LAK therapy. Our laboratory study showed the production of Interferon (IFN)-gamma and Tumor Necrosis Factor (TNF)-alpha by LAK cells when preincubated with RCC cells, which may indicate the mechanism of LAK cell-mediated antitumor activity in vivo. The study also showed that LAK cells as well as monocytes preincubated with the supernatant of LAK cells damaged normal endothelial cells in vitro, which suggested the possibility that LAK therapy risks increasing the frequency of brain metastasis by damaging the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Developmental expression of the vav protooncogene.

We have examined the expression of the vav protooncogene during mouse embryogenesis using RNase protection assays, in situ hybridization, and immunocytochemical analysis. vav gene transcripts were first detected in E11.5 embryos in the blood-forming islands and megakaryocytes of the fetal liver. During diversification of hematopoietic activity in the embryo, vav gene expression became down-regulated in the liver and activated in thymus and spleen. In newborn animals, vav expression was also confined to hematopoietic tissues, with the exception of the ameloblastic cell layer at the latest stages of tooth morphogenesis. In the adult, vav transcripts were found in spleen, thymus, lymph nodes, and bone marrow, but not in liver. In spleen, vav transcripts were concentrated in the white pulp areas, whereas in the red pulp, the vav transcripts appeared to be primarily localized in the megakaryocytes. In thymus, vav expression was found to be more abundant in the cortical areas than in the medulla. In agreement with these observations, purified thymic lymphocytes showed heterogeneous immunoreactivity against the Vav protein, whereas splenic lymphocytes and bone marrow-derived cells displayed rather uniform levels of expression. These observations suggest that the vav protooncogene plays an important role in the signal transduction pathways that regulate the development and maintenance of the hematopoietic system.

Animals↗
PubMed1986

Predictive assays for the therapy of rectum carcinoma.

Cytofluorometric DNA measurements showed that about 55% of rectum carcinoma (129 patients) had tumours with an abnormal DNA content (DNA aneuploidy). For patients with such a tumour the prognosis was worse than for patients with DNA diploid tumours. From the DNA histograms the number of S-phase cells was calculated. In tumours with the stage pT3, which disseminated to lymph nodes or metastasized, a higher number of S-phase cells was found than in tumours with the staging pT3N0M0. In all untreated tumours cells with micronuclei were found. This demonstrated cell loss. In most tumours this effect was considerable. The ratio:number of S-phase cells/number of cells with micronuclei may allow a rough estimate for cell turnover. In patients with a bad prognosis and in those patients who had a local recurrence after resection of the tumour this ratio was high. In 34 patients the parameters were measured before and after preoperative radiotherapy. In some tumours a rapid increase of S-phase cells occurred after irradiation, this effect might express repopulation. In these patients a local recurrence was frequently found. From the data obtained so far a prediction for local recurrences might be possible from the determination of nuclear protein bound SH-groups. The determination of micronuclei indicated that it can be used as a measure for radiation response in tumours. All parameters show a high variability between individual tumours. A further study is useful whether the measured parameters are suitable as predictors.

Adenocarcinoma↗
PubMed2005

Co-infected C57BL/6 mice mount appropriately polarized and compartmentalized cytokine responses to Litomosoides sigmodontis and Leishmania major but disease progression is altered.

This study examines the capacity of the mammalian host to fully compartmentalize the response to infection with type 1 vs. type 2 inducing organisms that infect different sites in the body. For this purpose, C57BL/6 mice were infected with the rodent filarial nematode Litomosoides sigmodontis followed by footpad infection with the protozoan parasite Leishmania major. In this host, nematode infection is established in the thoracic cavity but no microfilariae circulate in the bloodstream. We utilized quantitative ELISPOT analysis of IL-4 and IFN-gamma producing cells to assess cytokine bias and response magnitude in the lymph nodes draining the sites of infection as well as more systemic responses in the spleen and serum. Contrary to other systems where co-infection has a major impact on bias, cytokine ratios were unaltered in either local lymph node. The most notable effect of co-infection was an unexpected increase in the magnitude of the IFN-gamma response to L. major in mice previously infected with L. sigmodontis. Further, lesion development was significantly delayed in these mice. Thus, despite the ability of the immune system to appropriately compartmentalize the immune response, interactions between responses at distinct infection sites can alter disease progression.

Animals↗
PubMed2005

Quantitative molecular diagnosis of axillary drainage fluid for prediction of locoregional failure in patients with one to three positive axillary nodes after mastectomy without adjuvant radiotherapy.

PURPOSE: A quantitative multiple-marker reverse transcriptase (RT)-polymerase chain reaction (PCR) assay for sensitive detection of cancer cells in axillary drainage fluid was developed to examine whether the presence of cancer cells in axillary drainage fluid can be used as a predictor of locoregional recurrence (LRR) in patients with breast cancer who had T1/2 primary tumors and one to three positive axillary lymph nodes treated with modified radical mastectomy without adjuvant radiotherapy. METHODS AND MATERIALS: Axillary drainage fluid was collected from 126 patients with invasive ductal carcinoma of the breast who were treated with modified radical mastectomy and were found to have one to three positive axillary nodes. Cancer cells in axillary drainage fluid were detected by RT-PCR assay using primers specific for carcinoembryonic antigen (CEA) and cytokeratin-19 (CK-19) together with numerous clinicopathologic and treatment-related factors and were analyzed for their impact on LRR. RESULTS: A total of 38 patients suffered LRR during follow-up and the multimarker RT-PCR assays for CEA and CK-19 in the axillary drainage fluid both were positive in 34 patients (27.0%), of which 29 patients had LRR. In univariate analysis, the 5-year LRR-free survival showed higher rates in patients with PCR-negative findings in axillary drainage fluid (p<0.0001), age>or=40 years old (p<0.0001), tumor size<2.5 cm (p<0.0001), negative lymph-vascular space invasion (p=0.026), and T1 status (<0.0001); in multivariate analysis, PCR-positive findings together with age and tumor size were found to be independent predictors of LRR (all p<0.05). CONCLUSION: Multiplex RT-PCR assay for CEA and CK-19 was highly sensitive for detection and might be useful for prediction of LRR in such subgroup breast cancer patients.

Adult↗
PubMed2000

Cell-mediated immunity to tumor-associated antigens is a better predictor of survival in early stage breast cancer than stage, grade or lymph node status.

Cell-mediated immune (CMI) responses to tumor-associated antigens (TAA) in the early postoperative period were examined for correlations with disease recurrence and survival in a 13-year-prospective study of 77 stage 1 and 2 breast cancer patients treated with modified radical or radical mastectomy alone. Among the 21 patients who had positive lymphoproliferative tests using patients' peripheral blood mononuclear cells and autologous TAA of breast cancer cells, only one died from metastatic disease (5%). Among the 56 patients who had a negative test, 23 died from metastatic disease (41%). This difference is statistically significant (p = 0.002) Three other risk factors including tumor size, nodal status and cell differentiation patterns were also analyzed. When these three clinical-pathologic criteria were analyzed individually, none reliably predicted disease recurrence and survival. Nodal status was the most predictive clinical-pathologic risk factor, but was not significant (p = 0.089). The results of this study demonstrate the detection of CMI responses against autologous TAA by lymphoproliferative assays identifies a sub-set of stage 1 and 2 breast cancer patients who are at minimal risk of developing metastatic disease. This testing also identifies immunologically unreactive patients who are at risk for disease recurrence.

Antigens, Neoplasm↗
PubMed1999

Evaluation of S-100beta assays for the prediction of recurrence and prognosis in patients with AJCC stage I-III melanoma.

We performed prospective serial studies on 266 melanoma patients undergoing surgery for high risk primary or lymph node metastases to assess the predictive value for recurrence of melanoma of S-100beta detection in the serum using immunoradiometric assay (IRMA) or Immunoluminometric assay (LIA-mat). The tests for S-100beta were most frequently positive in the first 3 months after surgery. Results of the assays did not show a strong correlation with clinical stage of the disease. Studies on a cohort of 147 patients who had been followed for a minimum of 2 years post-surgery were carried out to assess the sensitivity of the assays for identifying patients who develop recurrence of their melanoma. The LIA-mat and IRMA assays detected S-100beta in the serum of 47.5% and 23%, respectively, of the subset of 61 patients who developed recurrence of disease. By Kaplan Meler analysis, patients positive for S-100beta by LIA-mat assay in the first 3 months post-surgery were shown to have an approximately 2.7 times shorter disease-free survival (DFS) period than patients negative for S-100beta. This was significant by log rank analysis. Multivariate analysis indicated that the presence of S-100beta was an independent prognostic determinant of DFS, and was independent of tumour thickness and lymph node status. This prospective analysis in a large number of patients suggests that assays for S-100beta in patients following surgical resection of AJCC stage I-III melanoma are of limited value for identifying patients who will develop recurrence of their disease. The results of the LIA-mat assays, but not the IRMA assays, do however provide an additional measure of prognosis that is independent of existing measures.

Biomarkers, Tumor↗
PubMed1997

Nuclear localization of RelB is associated with effective antigen-presenting cell function.

Dendritic cells (DC) are potent APCs that enter resting tissues as precursors and, after Ag exposure, differentiate and migrate to draining lymph nodes. The phenotype of RelB knockout mice implicates this member of the NF kappa B/Rel family in DC differentiation. To further elucidate the role of RelB in DC differentiation, mRNA, intracellular protein expression, and DNA binding activity of RelB were examined in immature and differentiated human DC, as well as other PB mononuclear cell populations. RelB protein and mRNA were detected constitutively in lymphocytes and in activated monocytes, differentiated DC, and monocyte-derived DC. Immunohistochemical staining demonstrated RelB within the differentiated lymph node interdigitating DC and follicular DC, but not undifferentiated DC in normal skin. Active nuclear RelB was detected by supershift assay only in differentiated DC derived from either PB precursors or monocytes and in activated B cells. These RelB+ APC were potent stimulators of the MLR. The data indicate that RelB expression is regulated both transcriptionally and post-translationally in myeloid cells. Within the nucleus, RelB may specifically transactivate genes that are critical for APC function.

Adult↗
PubMed1991

The effect of surgical timing within the fertility cycle on breast cancer outcome.

Murine studies have documented the relationship between surgical curability of a breast cancer and fertility cycle stage at the time of primary surgical resection. In a retrospective study of 41 premenopausal women with primary breast cancer followed for 6 to 14 years, disease recurrence was more frequent and more rapid in women whose initial tumor resection was performed during the perimenstrual period (days 0-6 and 21-36) than during the periovulatory period (days 7-20) of the menstrual cycle. Patients in both groups had disease of equal severity as measured by size of primary tumor, extent of lymph node involvement, estrogen and progesterone receptor assay determination, flow cytometry, and HER-2/neu gene amplification. To date, with 100% follow-up, 7 of the 19 perimenstrual patients (37%) have relapsed and 6 (32%) have died of metastatic disease. Only 3 of the 22 periovulatory patients (14%) have relapsed and only 1 (5%) has died of metastatic disease. These results, predicted by a murine experimental model, suggest that the endocrine milieu at the time of primary tumor resection impacts upon breast cancer prognosis.

Breast Neoplasms↗
PubMed2006

Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer.

Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.

Autopsy↗