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R S Berkowitz

Publications and source records attributed to R S Berkowitz.

At least 19 recordsLinked to original sources
PubMed2001

The clinical utility of liposomal doxorubicin in recurrent ovarian cancer.

OBJECTIVES: The aim of this study was to determine the efficacy and toxicity of single agent off-protocol, liposomal doxorubicin (Doxil Alza), in consecutive patients with recurrent ovarian cancer and to investigate the influence of HER-2/neu expression on response to liposomal doxorubicin. PATIENTS AND METHODS: Retrospective analysis of 72 consecutive patients treated, typically with liposomal doxorubicin 40 mg/m(2) q28 days between January 1997 and December 1998. Results. Twenty-nine patients (40%) had platinum- and taxane-resistant tumors. Nineteen patients (27%) responded with clinical or radiological evidence of response with reduction in CA-125 of >50%. One complete response (CR) and 7 partial responses (PRs) occurred in platinum- and taxane-resistant patients (radiological response (RR) 29%) and 8 PRs occurred in patients with visceral metastases (RR 28%). Time to progression was 5.3 (2.1-12.1) months. Only 7 dose delays (3%) and 20 dose reductions (8%) were necessary in 265 cycles of treatment. Hematological toxicity was generally mild with grade (Gr) > or =III neutropenia in 1 (2%), Gr > or =III thrombocytopenia in 1 (1%), and Gr > or =III anemia in 8 patients (11%). One patient (1%) was admitted with fever and neutropenia. Other toxicity was minimal with Gr > or =III mucositis occurring in 3 patients (4%). Gr > or =III cutaneous toxicity was seen in 6 patients (8%). Three patients (4%) had a >10% fall in ejection fraction but there was no unequivocal clinical heart failure. CONCLUSIONS: The data suggest that liposomal doxorubicin is an active drug in both taxane- and platinum-sensitive and resistant recurrent ovarian cancer. Liposomal doxorubicin is associated with tolerable toxicity and is particularly well tolerated in patients with multiple prior lines of treatment.

Adult↗
PubMed2000

Analysis of p73 in human borderline and invasive ovarian tumor.

p73 is a novel gene that has high sequence homology and similar gene structure to the tumor suppressor gene p53. We analysed p73 in seven ovarian carcinoma cell lines and a total of 63 human borderline and invasive ovarian tumor samples. Loss of heterozygosity at this locus was observed in 50% of invasive tumors but in none of the borderline tumors. Biallelic expression of the gene was observed in the heterozygous tumor tissues. Direct sequencing and single-strand conformation polymorphism analyses of the p73 cDNA sequence homologous to the highly mutatable region of p53 did not reveal any mutations. When compared to the primary cultures of normal human ovarian surface epithelial cells and immortalized cell lines, four of the seven ovarian carcinoma cell lines, 71% of the invasive tumors, and 92% of the borderline tumor tissues express elevated levels of p73 transcript. Except for the OVCA3 cell line, Western blot analysis of the nuclear extracts prepared from the cell lines showed concordant levels of p73 protein. Our analysis also demonstrated the expression of a spliced variant of p73 transcript with the omission of exon 2 solely in the cancer cell lines and invasive tumor tissues. This exon 2-spliced transcript would give rise to a truncated p73 protein without the N-terminal transactivation domain. In reminiscence of the dominant negative phenotype of the N-terminal truncated variants of another p53-related gene, p63, the expression of the truncated p73 variant form in ovarian tumors may play an important role in the pathogenesis of ovarian cancer.

Amino Acid Sequence↗
PubMed2000

BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis.

Papillary serous carcinoma of the peritoneum (PSCP) is believed to develop de novo from the peritoneal lining of the pelvis and abdomen. Although it is histologically indistinguishable from serous ovarian carcinoma, PSCP exhibits minimal or absent ovarian involvement and may even develop in a woman years after prophylactic oophorectomy. We have shown previously that patients with germ-line BRCA1 mutations who develop PSCP are more likely to have disease originating from multiple peritoneal sites compared with patients with wild-type BRCA1. In this study, we tested the hypothesis that BRCA1-related PSCP has a unique molecular pathogenesis. DNA was extracted from normal tissue and multiple tumor sites in patients with PSCP. BRCA1 and p53 gene mutations were screened for using single-strand conformation polymorphism. Loss of heterozygosity was determined at the BRCA1 and p53 loci. Immunohistochemical analyses of p53, epidermal growth factor receptor, erbB-2, erbB-3, erbB-4, and Bcl-2 expression were performed. We detected germ-line BRCA1 mutations in 11 (26%) of 43 PSCP patients. BRCA1 mutation carriers had a higher overall incidence of p53 mutations (89% versus 47%; P = 0.052), were more likely to exhibit multifocal or null p53 mutations (63% versus 7%; P = 0.014), and were less likely to exhibit erbB-2 overexpression (P = 0.013) than wild-type BRCA1 case subjects. We propose that the unique molecular pathogenesis of BRCA1-related PSCP may affect the ability of current methods to reliably prevent or detect this disease prior to metastasis.

BRCA1 Protein↗
PubMed2000

Genetic alterations of the WT1 gene in papillary serous carcinoma of the peritoneum.

OBJECTIVE: The Wilms' tumor (WT1) gene product is consistently detectable in both normal ovarian germinal epithelium and human mesothelium. Ovarian carcinomas frequently exhibit alterations in WT1 function. Papillary serous carcinoma of the peritoneum (PSCP) is believed to develop de novo from the peritoneal lining (mesothelium) of the pelvis and abdomen. The purpose of this study was to determine if genetic alterations of the WT1 gene are associated with the development of PSCP. METHODS: Normal and tumor tissue specimens were retrieved from patients with stage III and IV PSCP (n = 38) and serous epithelial ovarian carcinoma (n = 38). Immunohistochemistry was performed using the anti-WT1 (C-19) antibody. Loss of heterozygosity (LOH) was performed at the WT1 locus. Clinical data were obtained and correlated with molecular findings. RESULTS: Loss of normal WT1 expression was detected in 18 (51%) of 35 PSCP specimens and 18 (53%) of 34 ovarian carcinoma specimens. Six (27%) of 22 PSCP specimens and 3 (13%) of 24 ovarian carcinoma specimens had LOH at the WT1 locus (P = 0.27). Normal WT1 gene expression was maintained in 86% of tumors exhibiting LOH. Genetic alterations of the WT1 gene were not predictive of survival, nor were they associated with other clinical or molecular factors. CONCLUSIONS: Genetic alterations of the WT1 gene are associated with the development of PSCP. The loss of normal WT1 gene expression is a common event in both PSCP and advanced ovarian carcinoma, likely resulting from down-regulation by other regulatory factors-not from inactivating gene mutation and subsequent allelic loss.

Adult↗
PubMed2000

ras gene activation and infrequent mutation in papillary serous carcinoma of the peritoneum.

OBJECTIVE: The ras genes are a well-studied family of proto-oncogenes whose involvement in many cancers has been delineated. However, K-ras mutations have not previously been examined in papillary serous carcinoma of the peritoneum (PSCP), a tumor which resembles serous epithelial ovarian carcinoma (SEOC) both in histology and epidemiology. In this study we examine the role of the K-ras oncogene in PSCP compared to SEOC. METHODS: Using single-strand conformational polymorphism analysis and cycle sequencing protocols, we evaluated our collection of 51 cases of PSCP for K-ras mutations and compared these findings with the experience in SEOC. We then examined 5 cases of PSCP for activation of ras proteins and MAP kinase to evaluate the potential involvement of the ras pathway in PSCP tumorigenesis. RESULTS: We found only one K-ras mutation in our 51 cases (2%) of PSCP compared to three mutations in 46 cases (6.5%) of high-grade, late-stage SEOC. This was not significantly different (P > 0.10). In the single PSCP case with a K-ras mutation, the mutation was found in only one of five tumor sites tested. All four mutations involved a single nucleotide alteration in codon 12 (GGT to GTT, Gly to Val). To evaluate the ras pathway in PSCP, we used the known activated ras binding domain on Raf-1 to perform an assay to test for activated ras. We identified ras activation in 4 of 5 PSCP cases tested and, to confirm that the activation was functional, we tested and found similar activation of MAP kinase, a downstream mediator for K-ras expression. CONCLUSIONS: K-ras mutations occur at low rates in both PSCP and high-grade, late-stage SEOC, and therefore K-ras mutations are not involved in the development of these two diseases. Finding the mutation in only one of multiple tumor sites in the PSCP case supports growing evidence for a multifocal origin of PSCP. Our findings of ras activation in four of five cases of PSCP suggest that ras activation by mechanisms other than genetic mutation is important for PSCP tumorigenesis.

Cystadenocarcinoma, Papillary↗
PubMed2000

Expression of epidermal growth factor receptor-related family products in gestational trophoblastic diseases and normal placenta and its relationship with development of postmolar tumor.

OBJECTIVE: The goal of this work was to study the expression of epidermal growth factor receptor (EGFR) and c-erbB-3 and c-erbB-4 oncogenes in gestational trophoblastic diseases and normal first-trimester placenta. STUDY DESIGN: Paraffin sections of 16 cases of partial mole, 25 cases of complete mole, 10 cases of gestational choriocarcinoma, and 11 cases of therapeutic abortion were studied immunohistochemically for EGFR, c-erbB-3, and c-erbB-4 proteins. The presence of EGFR mRNA was studied using in situ hybridization. RESULTS: Staining for EGFR was detected immunohistochemically in all cell types in gestational trophoblastic diseases and normal placenta. In situ hybridization for EGFR mRNA correlated with immunostaining for EGFR in all tissues studied. All 10 cases of choriocarcinoma exhibited strong immunoreactivity for EGFR. The levels of expression of EGFR in choriocarcinoma and syncytiotrophoblasts and cytotrophoblasts in complete mole were significantly greater than those in syncytiotrophoblasts and cytotrophoblasts in both normal placenta and partial mole (P < 0.01, P < 0.01). Expression of c-erbB-3 did not significantly differ among placental and gestational trophoblastic disease tissues and trophoblastic cell types except for significantly increased expression in choriocarcinoma as compared with cytotrophoblasts of partial mole (P = 0.02). The placenta, complete and partial mole, and choriocarcinoma tissues demonstrated similar immunoreactivity for c-erbB-4. Strong immunostaining for EGFR (P = 0.02) and c-erbB-3 (P < 0.01) in extravillous trophoblasts of complete mole was found to be significantly correlated with the development of persistent postmolar gestational trophoblastic tumor. CONCLUSION: The EGFR-related family of oncogenes may be important in the pathogenesis of gestational trophoblastic diseases. The increased expression of EGFR and c-erbB-3 in complete mole may also influence the development of persistent gestational trophoblastic tumor.

Adult↗
PubMed2000

Differential expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 protein and mRNA in epithelial ovarian tumors.

OBJECTIVE: Matrix metalloproteinase-9 (MMP-9) can degrade gelatin and type IV collagen and is known to play an important role in tumor cell invasion across the basement membrane. The tissue inhibitor of metalloproteinase-1 (TIMP-1) is able to prevent activation of pro-MMP-9 and forms a 1:1 complex with the active form of MMP-9. The aim of the present study was to investigate the expression of MMP-9 and TIMP-1 in benign, borderline, and invasive epithelial ovarian tumors. MATERIALS AND METHODS: A total of 90 patients with epithelial ovarian tumor were treated at the Brigham and Women's Hospital and were used as the study population. Immunohistochemistry and in situ hybridization were performed to detect protein and mRNA expression of MMP-9 and TIMP-1. RESULTS: In the 90 epithelial ovarian tumors tested, MMP-9 expression in tumor cells was found to be significantly enhanced in serous and mucinous ovarian carcinomas compared with benign and borderline tumors. We also observed the immunostaining of MMP-9 in stromal cells of benign, borderline, and invasive epithelial ovarian tumors. Moreover, the expression levels of TIMP-1 in tumor cells were significantly higher in borderline and invasive ovarian tumors than in benign tumors. CONCLUSION: Using an in situ hybridization technique, we disclosed a direct correlation between the presence of mRNA and protein expression for both MMP-9 and TIMP-1. The present data suggest that high levels of MMP-9 protein in invasive epithelial ovarian carcinoma are strongly associated with tumor cell invasion. Enhanced expression of TIMP-1 protein in borderline and invasive tumors indicates that endogenous TIMP-1 protein may play a paradoxical role in ovarian tumor progression.

Cystadenocarcinoma, Mucinous↗
PubMed2000

Bcl-2 and p53 protein expression, apoptosis, and p53 mutation in human epithelial ovarian cancers.

Bcl-2 and p53 gene products have been both linked to cell death by apoptosis. In the present study, we examined the relationship of Bcl-2 and p53 protein expression, p53 mutation and apoptosis in normal human ovaries and different types of human ovarian epithelial tumors by immunohistochemical localization, in situ terminal transferase-mediated dUTP nick end labeling and polymerase chain reaction-single strand conformation polymorphism. It was found that Bcl-2 expressed strongly in the surface epithelium of normal ovaries and benign and borderline ovarian tumors but weakly in the malignant tumors. On the contrary, strong protein expression of p53 was found in 54% (25/46) of the malignant epithelial tumors examined but similar expression of p53 was not observed in borderline and benign tumors and normal ovarian surface epithelium. A significant inverse correlation between Bcl-2 and p53 expression was found in the malignant ovarian tumors examined. p53 gene mutation at exons 5-11 was however not a pre-requisite for p53 expression in both borderline and malignant tumors. Apoptotic activities, as reflected by apoptotic indices, were low in normal ovarian surface epithelium and benign tumors but were increased in borderline and malignant tumors, with the highest average apoptotic index found in grade III malignant tumors. Statistical analyses showed a positive correlation between apoptosis and p53 expression, but similar correlation was not found between apoptosis and Bcl-2 expression. Our results also indicate that although expression of Bcl-2 is important during ovarian carcinogenesis, the Bcl-2 protein may have other roles to play apart from being a modulator of apoptosis in human ovarian epithelial cancers.

Apoptosis↗
PubMed2000

Identification of a novel 9 cM deletion unit on chromosome 6q23-24 in papillary serous carcinoma of the peritoneum.

To define regions of deletion on chromosome 6q in papillary serous carcinoma of the peritoneum (PSCP), we analyzed 103 tumor tissues from 53 patients by using 11 polymorphic microsatellite markers spanning loci from 6q23 to 6q27. Allelic losses on 6q were observed in 42 of 53 (79.2%) cases. We identified 3 distinct regions with a high percentage (>40%) of loss of heterozygosity. The first region is located at 6q23-24 and defined by D6S311 (15 of 35 informative cases, 42.9%). Detailed deletion mapping of chromosome 6q23-24 in these tumor samples identified a novel 9 cM minimal deletion region flanked by D6S250 and ESR. The second one is located at 6q25.1-25.2 and defined by D6S448 (17 of 36 informative cases, 47.2%). A second minimal deletion region of 4 cM was flanked by D6S420 and D6S442. The third region is located at 6q27 and defined by D6S297 (9 of 19 informative cases, 47.4%). Comparing these results with our cases of advanced staged invasive serous epithelial ovarian carcinoma (SEOC), we observed that allelic losses at D6S311 (6q23) and D6S149 (6q27) were significantly higher for PSCP than for SEOC. The pattern of allelic loss at each tumor site within an individual patient was also studied. A total of 36 cases displayed allelic loss for at least 1 of multiple tumor sites, and 35 of these patients exhibited nonidentical patterns of allelic loss at various tumor sites of the same patient. Furthermore, an alternating pattern of allelic loss in the same patient was identified in 3 of 53 patients studied. These results show that allelic losses on 6q are very frequent in PSCP, and we show 2 discrete minimal deletion regions on 6q, suggesting the existence of at least 2 tumor suppressor genes within 6q that may be involved in the pathogenesis of PSCP. In addition, the finding of different patterns of allelic loss at different tumor sites within the same patient indicate a mutifocal origin in some PSCP cases. These results provide strong evidence to support our previous reports that PSCP is a multifocal disease entity.

Chromosome Deletion↗
PubMed2000

Sonographic appearance of first trimester complete hydatidiform moles.

OBJECTIVE: Complete hydatidiform moles are now being diagnosed earlier in gestation, thus the clinical presentation and pathologic findings of complete molar pregnancy have changed. We studied the sonographic appearance of first trimester moles and the ability of ultrasound to detect them. METHODS: We reviewed the sonographic interpretation and sonograms, when available, from all patients with first trimester complete moles diagnosed at our institution from January 1988 to March 1996. RESULTS: Of the 24 patients in our study, the mean gestational age at time of the sonogram was 8.7 +/- 2.0 weeks (mean +/- SD) with a range of 5.7-12.3 weeks. The initial sonographic interpretation was a complete mole in 17 (71%) cases, partial mole versus failed pregnancy in two (8%), and failed pregnancy in five (21%) cases. Of the 22 patients with sonograms available for review, interpretation on review of the images was a complete mole in 18 (82%) cases, partial mole versus failed pregnancy in one (5%), and failed pregnancy in three (14%) cases. The typical sonographic appearance of a first trimester complete mole was a complex, echogenic, intra-uterine mass containing many small cystic spaces. CONCLUSION: The majority of first trimester complete moles demonstrate a typical ultrasound appearance such that the diagnosis can be made with ultrasound in most cases.

Adult↗
PubMed2000

Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy.

PURPOSE: To review the findings at prophylactic oophorectomy of a series of women who presented to a familial breast and ovarian cancer clinic. MATERIALS AND METHODS: Data from medical charts, operative notes, and pathology reports were collected on women who had undergone prophylactic oophorectomies because of the elevated risk of ovarian cancer. Because only a subset of patients underwent BRCA1 and BRCA2 testing, each patient's risk of hereditary predisposition was calculated using the Berry-Parmigiani model and family history data. RESULTS: From June 1989 to December 1998, 50 women seen at our clinic underwent prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%. Among this group, four incidental tumors were found (four of 33, or 12%); one tumor was noted at the time of surgery and three were noted only in the final pathology. Two patients had microscopic, poorly differentiated serous adenocarcinomas in multiple sites on both ovaries. A third patient had a bilateral serous borderline tumor with micropapillary features. The fourth patient had a microscopic serous borderline ovarian tumor. All four patients had germline BRCA1 or BRCA2 mutations, and three had unremarkable transvaginal ultrasonography examinations within 6 months before prophylactic surgery. CONCLUSION: Foci of malignant tumor are not uncommon in prophylactic oophorectomies performed in women at very high risk for ovarian cancer and may not be detected on ultrasonograms. Surgeons should have a high suspicion of finding cancer in these women at the time of prophylactic surgery, and careful pathologic assessment of the specimens should be conducted.

Adult↗
PubMed2000

Distinct allelic loss patterns in papillary serous carcinoma of the peritoneum.

Tumor and normal tissues from 55 patients with papillary serous carcinoma of the peritoneum (PSCP) were analyzed. Polymerase chain reaction amplification of tandem repeat polymorphism was used to screen for loss of heterozygosity (LOH). We mapped 22 oligonucleotide primers to chromosomes 1p, 3p, 6q, 7q, 9p, 11p, 17p, 17q, and Xq. Germline BRCA1 mutation status of 43 patients was determined previously. High frequencies (> 30%) of LOH in PSCP were observed on 6q, 9p, 17p, 17q, and Xq. Compared with allelic loss of serous epithelial ovarian carcinoma (SEOC), the frequency of LOH was significantly lower in PSCP on 1p, 7q, 11p, 17p, and 17q. Of 43 cases screened for germline BRCA1 mutations, 9 cases were identified with mutations. The frequencies of LOH were not significantly different among the BRCA1-related and BRCA1-unrelated PSCP cases. The high LOH rate identified on 6q, 9p, 17p, 17q, and Xq in PSCP suggests that candidate tumor suppressor genes residing in these regions may be important for the development of the tumor. Compared with allelic loss of SEOC, PSCP exhibits a significantly lower frequency of LOH on chromosomes 1p36, 7q31.3, 11p15.1, 17p13.1, and 17q21. An increase in susceptibility to the acquisition of allelic loss in BRCA1-related PSCP cannot be identified.

Alleles↗
PubMed2000

Recent advances in gestational trophoblastic disease.

Recent advances have increased our understanding of gestational trophoblastic disease, and epidemiologic studies have demonstrated that there are important differences in risk factors for complete and partial mole. Complete moles are now increasingly being diagnosed in the first trimester, affecting their clinical presentation and pathologic characteristics. While important advances have been made in chemotherapy, it is now recognized that etoposide is associated with a risk of second tumors. Several studies have advanced understanding of the molecular biology of gestational trophoblastic disease, and this is important for the eventual development of new and innovative therapy.

Antineoplastic Agents↗
PubMed2000

Management of gestational trophoblastic diseases: subsequent pregnancy experience.

Patients with gestational trophoblastic disease (GTD) can usually achieve complete sustained remission while retaining their fertility even in the presence of wide-spread metastasis. Following complete and partial mole, our patients had 1,239 and 205 later pregnancies, respectively, which resulted in 68.6% and 74.1% term live births, respectively. Patients with either type of hydatidiform mole have, in general, a normal later pregnancy experience. After one molar pregnancy, the risk of a molar pregnancy in a later conception was about 1%. Our patients who received chemotherapy for persistent gestational trophoblastic tumor had 522 later pregnancies, which resulted in 358 (68.6%) term live births and only 10 (2.5%) major and minor congenital anomalies. Data from other centers involving 2,598 later pregnancies also indicate that after chemotherapy patients can generally anticipate a normal future reproductive outcome.

Female↗
PubMed1999

Oral contraceptive use and risk of gestational trophoblastic tumors.

BACKGROUND: Gestational trophoblastic disease refers to a spectrum of rare benign and malignant gynecologic disorders whose pathogenesis is not well understood. Recent studies from China and the United States have raised the hypothesis that long-term use of oral contraceptives before conception may increase the risk of gestational trophoblastic tumors. A multicenter case-control study of gestational trophoblastic tumors was undertaken to test this hypothesis. METHODS: Telephone interviews were conducted with 235 case patients, including 50 with gestational choriocarcinoma, and 413 control subjects matched on recentness of pregnancy, age at pregnancy, and area of residence. Relative risks (odds ratios) were computed by conditional logistic regression. Reported P values are two-sided. RESULTS: The relative risk estimate for ever having used oral contraceptives before the index pregnancy was 1.9 (95% confidence interval [CI] = 1.2-3.0), and the risk increased with duration of use (P for trend = .05). The estimate was highest for women who used oral contraceptives during the cycle in which they became pregnant (relative risk = 4.0; 95% CI=1.6-10), but there was no consistent pattern according to the time interval since last use. Separate analyses of choriocarcinoma and persistent mole yielded similar results, i.e., the relative risk estimates for oral contraceptive use were 2.2 (95% CI=0.8-6.4) and 1.8 (95% CI=1.0-3.0), respectively. Control for the number of sexual partners, which was independently associated with risk (P for trend = .05), did not materially change the results. CONCLUSIONS: This study, the largest to date, indicates that long duration of oral contraceptive use before conception increases the risk of gestational trophoblastic tumors. These findings may provide clues to the pathogenesis of this rare disease. Changes in use of oral contraceptives are not warranted, however, because the incidence attributable to oral contraceptive use is very low.

Adult↗
PubMed1999

A new human topoisomerase III that interacts with SGS1 protein.

Eukaryotic DNA topoisomerase III was first identified by studying the hyper-recombination and slow growth phenotypes of yeast mutants. Topoisomerase III interacts with DNA helicase SGS1 and the two proteins are involved in DNA recombination, cellular aging and maintenance of genome stability. A human homolog of topoisomerase III has previously been identified. Here we report the identification of cDNAs and the determination of gene structure for a second human topoisomerase III gene. This novel gene expresses three alternatively spliced transcripts, which encode gene products different in the putative DNA-binding C-termini. The largest gene product of the novel topoisomerase III was expressed and shown to interact with SGS1 protein and partially rescue the slow growth defect of a yeast topoisomerase III mutant. The presence of more than one human topoisomerase III is reminiscent of mammalian topoisomerase II, which has two genetically distinct isoforms with different expression patterns and probably different functions in mammalian cells.

Amino Acid Sequence↗
PubMed1999

Differential expression of NF1 type I and type II isoforms in sporadic borderline and invasive epithelial ovarian tumors.

The NF1 gene, a putative tumor suppressor gene, contains a GAP related domain (GRD) which accelerates hydrolysis of ras-bound GTP to GDP, thereby converting the ras oncogene from its active to inactive form. Two forms of the NF1 GRD transcript (Type I and Type II) are differentially expressed in neuroectodermal tumor tissue relative to differentiated neural cells, and in gastric cancer cell lines relative to normal stomach mucosa. We measured relative expression of NF1 Type II and Type I isoforms in cultured normal and malignant human ovarian surface epithelial cells(HOSE) and in invasive and borderline ovarian tumor tissue. We demonstrated an 11-fold increase in Type II:Type I ratio in 7 HOSE cultures relative to eight ovarian cancer cell lines. Our findings indicate a significant decrease in Type II isoform expression and increase in Type I expression in ovarian cancer cells and tumor tissue relative to HOSE cells. We also demonstrate an increase in Type II:Type I ratio, and a decrease in cell proliferation rate in three ovarian cancer cell lines on treatment with retinoic acid. We propose that differential expression of the NF1 Type I and Type II isoforms is related to cellular differentiation in ovarian epithelial cancer and strategies based on alteration in NF1 isoform expression may have therapeutic potential in ovarian malignancies.

Adenocarcinoma↗