Biomedical subjects

H Hibshoosh

Publications and source records attributed to H Hibshoosh.

At least 19 recordsLinked to original sources

PubMed2002

Fighting colorectal cancer: molecular epidemiology differences among Ashkenazi and Sephardic Jews and Palestinians.

BACKGROUND: To evaluate and compare differences in the molecular genetics among high-risk (Ashkenazi Jews), intermediate-risk (Sephardic Jews) and low-risk (Palestinians) groups for colorectal cancer who live in the same geographical region. PATIENTS AND METHODS: The 1995-1996 records from the Tel Aviv Medical Center and Muqased hospital (East Jerusalem) randomly identified patients with colorectal cancer. There were 25 patients from each ethnic group. Epidemiological data were obtained from interviews with the patients and from their hospital charts. The levels of cyclin D1, beta-catenine, p27, p53, Ki-67 and Her-2/neu proteins were determined by immunohistochemistry. The main outcome measures were the association between gene expression and colorectal incidence in the different ethnic groups. RESULTS: Ashkenazi Jews have the highest rate of colorectal cancer, and are diagnosed at an early stage compared with Palestinians (72% and 33% of the cases are in Dukes' A and B, respectively), and, hence, this may explain the better 5-year survival rate among this group. Sephardic Jews are diagnosed at a more advanced stage, the tumors are poorly differentiated and they lack p27. Palestinians have significantly higher cyclin D1 levels. There was a statistically significant inverse correlation between the expression of beta-catenine and cyclin D1, as well as p53 and p27 (P <0.05). CONCLUSIONS: Increased expression of cyclin D1, p53, Ki-67, beta-catenine and Her-2/neu, and decreased expression of p27 may be important events in the three ethnic groups with colorectal cancer. The lower mortality rate among Ashkenazi Jews may be partially explained by their better molecular biology profile.

Aged↗

PubMed2001

Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus.

Neoplastic progression in Barrett's esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27(kip1) protein, but did not display appreciable nuclear staining for p16(kip4), p21(cip1) or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16(kip4) (74%), p21(cip1) (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16(kip4) and cyclin E, and p21(cip1) and p27(kip4) with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.

Adult↗

PubMed2000

Immunohistochemical analysis of polycyclic aromatic hydrocarbon-DNA adducts in breast tumor tissue.

Environmental carcinogens may play a role in the etiology of breast cancer, but the extent of their contribution is not yet defined. The aims of this study were to determine whether polycyclic aromatic hydrocarbon (PAH)-DNA adducts could be detected in stored paraffin blocks of breast tumor tissue (n=147) with an immunoperoxidase technique and whether they correlated with smoking history and/or mutant p53 protein expression. There was no significant difference in mean relative nuclear staining intensity in non-smokers (444+/-90, n=75), ever smokers (435+/-91, n=72), and current smokers (456+/-98, n=35). In either current or ever smokers, PAH-DNA adducts were non-significantly elevated in those with greater compared with lower exposure in relation to age at started smoking, years of smoking, cigarettes per day, and pack years. DNA damage levels were not elevated in tissues with compared with those without mutant p53 protein expression. These data demonstrate that immunohistochemical methods can be used to monitor DNA damage levels in archived breast tissues.

Adult↗

PubMed2000

Activation of c-K-ras mutations in human gastrointestinal tumors.

BACKGROUND & AIMS: Ras genes are the most frequently detected oncogenes in human malignancies. Data regarding the frequency of c-K-ras mutations in esophageal, gastric, and small bowel tumors are limited and controversial. METHODS: DNA was extracted from 262 formalin-fixed, paraffin-embedded sections of gastrointestinal samples and tumors, including Barrett's esophagus, esophageal squamous cell carcinomas and adenocarcinomas, and small and large bowel adenomas and adenocarcinomas. The presence of c-K-ras codon 12 mutations was determined using a nonradioactive polymerase chain reaction-based restriction fragment length polymorphism assay. RESULTS: c-K-ras mutations were detected in 1 of 39 (2%) patients with Barrett's esophagus, 1 of 21 (5%) adenocarcinomas, 0 of 27 squamous cell carcinomas of the esophagus, and 1 of 32 (3%) gastric adenocarcinomas. It was also present in 8 of 20 (40%) and 10 of 28 (36%) small bowel adenomas and adenocarcinomas, respectively. Similar numbers were observed in 10 of 25 (40%) large bowel adenomas and 11 of 30 adenocarcinomas (37%). Mutations were not associated with age, gender, histology, grade, stage, location, or mortality. CONCLUSIONS: The frequency of codon 12 c-K-ras mutations in small and large bowel tumors is approximately 10-fold higher than that of tumors in the upper gastrointestinal tract.

Adenocarcinoma↗

PubMed2000

Chronic Helicobacter pylori infection induces an apoptosis-resistant phenotype associated with decreased expression of p27(kip1).

Helicobacter pylori infection is associated with the development of gastric cancer. In short-term coculture with AGS gastric cells, H. pylori inhibits cell cycle progression and induces dose-dependent apoptosis. Based on the concept that an imbalance between proliferation and apoptosis may contribute to the emergence of gastric cancer, we chronically exposed AGS cells to H. pylori as a model of chronic exposure in humans. The AGS derivatives selected by this process were stably resistant not only to H. pylori-induced apoptosis but also to apoptosis induced by other enteric bacteria and by several toxic agents including radiation and cancer chemotherapy. Like the parental AGS cells, the derivatives underwent G(1)/S-phase cell cycle inhibition in response to H. pylori. The AGS derivatives displayed a marked decrease in cellular levels of the cell cycle control protein p27(kip1). We found a similar decrease in epithelial cell p27(kip1) expression in gastric biopsy specimens from H. pylori-infected patients. These findings are consistent with observations that link decreases in the p27(kip1) level to increased susceptibility to cancer in mice with p27(kip1) deleted and to a poor prognosis of gastric cancer in humans. This is the first demonstration that bacterial infection can lead to apoptosis resistance and to cross-resistance to other inducers of apoptosis such as bacteria, chemotherapeutic agents, and radiation. The development of apoptosis resistance and downmodulation of p27(kip1) may contribute to the increased risk for gastric cancer observed in humans chronically exposed to H. pylori.

Apoptosis↗

PubMed2000

Estrogen and progesterone receptor-negative T11 vertebral hemangioma presenting as a postpartum compression fracture: case report and management.

OBJECTIVE AND IMPORTANCE: Pregnancy-related vertebral hemangioma compressive myelopathy is a rare occurrence that tends to arise in the upper thoracic and lower cervical spine, peaks during the third trimester, and remits after parturition. Whether corticosteroid receptors play a role in the pathogenesis of these lesions is unknown. Most of these lesions have been managed with posterior decompression. CLINICAL PRESENTATION: A 29-year-old woman presented with acute-onset lower-extremity weakness and sensory loss immediately after parturition. INTERVENTION: We used a retropleural approach for anterior decompression and fusion, followed by radiation therapy. Immunohistochemical analysis of estrogen and progesterone receptor expression was performed. CONCLUSION: We report an unusual case of lower thoracic postpartum vertebral hemangioma compressive myelopathy caused by a parturition-related compression fracture. Results of tests for corticosteroid receptors were negative, which implicated a hemodynamic rather than hormonal cause for disease progression.

Adult↗

PubMed2000

The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer.

A number of polycyclic aromatic hydrocarbons (PAH) are widespread environmental contaminants that cause mammary cancer experimentally. We investigated whether exposure and susceptibility to PAH, as measured by PAH-DNA adducts in breast tissue, are associated with human breast cancer. We carried out a hospital-based case-control study using immunohistochemical methods to analyze PAH-DNA adducts in tumor and nontumor breast tissue from cases and benign breast tissue from controls. The subjects were white, African-American and Latina women without prior cancer or treatment, including 119 women with breast cancer and 108 with benign breast disease without atypia. PAH-DNA adducts measured in breast tumor tissue of 100 cases and in normal tissue from 105 controls were significantly associated with breast cancer (OR=4.43, 96% CI 1.09-18.01) after controlling for known breast cancer risk factors and current active and passive smoking, and dietary PAH. There was substantial interindividual (17-fold) variability in adducts overall, with 27% of cases and 13% of controls having elevated adducts. The odds ratio for elevated adducts in tumor tissue compared with control tissue was 2.56 (1. 05-6.24), after controlling for potential confounders. Adduct levels in tumor tissue did not vary by stage or tumor size. Among 86 cases with paired tumor and nontumor tissue, adducts levels in these two tissues were highly correlated (r=0.56, P<0.001). However, the corresponding associations between case-control status and adducts measured in nontumor tissue from 90 cases and in normal tissue from 105 controls were positive but not statistically significant. Overall, neither active nor passive smoking, or dietary PAH were significantly associated with PAH-DNA adducts or breast cancer case-control status. These results suggest that genetic damage reflecting individual exposure and susceptibility to PAH may play a role in breast cancer; but more research is needed to determine whether the findings are relevant to causation or progression of breast cancer.

Adult↗

PubMed1999

Induction of autophagy and inhibition of tumorigenesis by beclin 1.

The process of autophagy, or bulk degradation of cellular proteins through an autophagosomic-lysosomal pathway, is important in normal growth control and may be defective in tumour cells. However, little is known about the genetic mediators of autophagy in mammalian cells or their role in tumour development. The mammalian gene encoding Beclin 1, a novel Bcl-2-interacting, coiled-coil protein, has structural similarity to the yeast autophagy gene, apg6/vps30, and is mono-allelically deleted in 40-75% of sporadic human breast cancers and ovarian cancers. Here we show, using gene-transfer techniques, that beclin 1 promotes autophagy in autophagy-defective yeast with a targeted disruption of agp6/vps30, and in human MCF7 breast carcinoma cells. The autophagy-promoting activity of beclin 1 in MCF7 cells is associated with inhibition of MCF7 cellular proliferation, in vitro clonigenicity and tumorigenesis in nude mice. Furthermore, endogenous Beclin 1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissue, but is expressed ubiquitously at high levels in normal breast epithelia. Thus, beclin 1 is a mammalian autophagy gene that can inhibit tumorigenesis and is expressed at decreased levels in human breast carcinoma. These findings suggest that decreased expression of autophagy proteins may contribute to the development or progression of breast and other human malignancies.

Animals↗

PubMed1999

Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice.

Cdc25 phosphatases activate cyclin-dependent kinases (Cdks) by dephosphorylating critical phospho-tyrosine and phospho-threonine residues on these proteins. Several types of studies indicate that Cdc25s can enhance cell proliferation and oncogenesis. Furthermore, overexpression of Cdc25A and/or B have been detected in several types of primary human cancers, including breast cancers. To further assess the oncogenic capacity of Cdc25B in vivo, we have generated transgenic mice that overexpress Cdc25B in the mammary epithelium, driven by the MMTV - LTR promoter. Although these mice are grossly normal for up to 18 months, the ectopic expression of Cdc25B in their mammary glands increases the susceptibility of these mice to induction of mammary tumors by the carcinogen 9,10-dimethyl-1, 2-benzanthracene (DMBA).

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1999

Overexpression of cyclin D1 occurs in both squamous carcinomas and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach.

Increased expression of the cyclin D1 gene frequently occurs in human squamous carcinomas of the esophagus. However, the expression of cyclin D1 has not been previously examined in detail in adenocarcinomas of the esophagus or stomach. Therefore, we examined, in parallel, the expression of cyclin D1 in both squamous and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach. The level of expression of the cyclin D1 protein was assessed by immunohistochemistry in 39 esophageal and 34 gastric carcinomas and correlated with clinical and pathology parameters. Within the esophagus, 71% of the squamous carcinomas and 64% of the adenocarcinomas were positive for increased cyclin D1 nuclear staining. For adenocarcinomas of the stomach, the overall positive rate was 47%; in the gastric cardia, the rate was 44%, and in other regions of the stomach, it was 50%. In esophageal and gastric adenocarcinomas of the intestinal type, increased expression of cyclin D1 was seen in 70% of the samples, whereas with the diffuse type only 13% were positive (P < .01). Tumors from patients older than the median age of 67 years were more frequently positive than tumors from patients younger than 67 years (74% v 42%, respectively) (P < .01). Positive staining was also seen more frequently in well and moderately differentiated tumors than in poorly differentiated tumors (74% v 49%, respectively) (P < .05). Cytoplasmic staining for cyclin D1 was noted in 22% of the tumors, of various types. Therefore, increased expression of cyclin D1 frequently occurs in both adenocarcinomas and squamous carcinomas of the esophagus, and in adenocarcinomas of the stomach. The increased expression in adenocarcinomas is especially frequent in the intestinal-type lesions.

Adenocarcinoma↗

PubMed1999

Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women.

p53 mutations may be a fingerprint for cigarette smoking and other environmental carcinogens, including breast carcinogens. This study was undertaken to explore whether p53 mutations are associated with environmental or other suspected or established risk factors for breast cancer. p53 protein detection by immunohistochemistry (which is more easily quantified in large epidemiological studies than are mutations, and are highly correlated with them) was determined for 378 patients from a case-control study of breast cancer. In this population-based sample of women under the age of 45 years, 44.4% (168/378) of the cases had p53 protein detected by immunohistochemistry (p53+). Polytomous logistic regression was used to calculate the odds ratios (ORs) for p53+ and p53- breast cancer, as compared with the controls, in relation to cigarette smoking and other factors. The ratio of the ORs was used as an indicator of heterogeneity in risk for p53+ versus p53- cancer. The ratio of the ORs in a multivariate model was substantially elevated among women with a greater than high school education [2.39; 95% confidence interval (CI), 1.43-4.00], current cigarette smokers (1.96; 95% CI, 1.10-3.52), and users of electric blankets, water beds, or mattresses (1.78; 95% CI, 1.11-2.86). Nonsignificant heterogeneity was noted for family history of breast cancer and ethnicity but not for other known or suspected risk factors. Coupled with the strong biological plausibility of the association, our data support the hypothesis that in breast cancer, as with other tumors, p53 protein immunohistochemical detection may be associated with exposure to environmental carcinogens such as cigarette smoking.

Adult↗

PubMed1999

Oral contraceptive use and other risk factors in relation to HER-2/neu overexpression in breast cancer among young women.

This study was undertaken to explore whether the incidence of breast tumors that overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated with oral contraceptives (OCs) and other factors than is the incidence of tumors that do not (HER-2/neu-). In a population-based sample of women <45 years, 42.9% (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as assessed by immunohistochemistry in archived tissue. Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for HER-2/neu+ and HER-2/neu-breast cancer, as compared with 462 population-based controls, in relation to OCs and other factors. The ratio of the ORs (HER-2/neu+ versus HER-2/neu-tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83-2.00). Among early pill users (< or =18 years of age) heterogeneity was apparent (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99; 95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors, heterogeneity increased to 5-fold. For other risk factors, there was no marked heterogeneity between + and - tumors for HER-2/neu. In summary, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the odds ratio for +tumors twice that for -tumors.

Adult↗

PubMed1999

Wild-type p53 epitope naturally processed and presented by an HLA-B haplotype on human breast carcinoma cells.

To broaden the clinical applicability of peptide-based immunotherapy in breast cancer, there is a need to identify further tumor-associated peptide epitopes that are specific for HLA alleles, in addition to HLA-A2. The HLA-B44 haplotype is one of the most common HLA-B haplotypes, occurring in 10-20% of the population. We performed the structural characterization of HLA class I-bound self-peptides presented by a human breast cancer cell line with a HLA-A68, A32, B40, B44 haplotype, to identify potential tumor-specific antigens. Of 13 sequenced peptides, 1 peptide had the HLA-A68 peptide binding motif and 12 peptides had the HLA-B40, B44 peptide binding motif. One of the latter peptides, FEVRVCACPG, shared 100% homology to residues 270-279 of wild-type P53 protein. Our study, thus, provides direct evidence for the natural processing and presentation of p53 epitope 270-279 by HLA-B40, B44-bearing human breast tumor cells. Epitopes spanning this region of P53 may have potential use for immunotherapy in patients expressing HLA-A2 and -B44 supertypes.

Adenocarcinoma↗

PubMed1999

Abnormalities in the expression of cell cycle-related proteins in tumors of the small bowel.

Tumors of the small bowel are quite rare for unknown reasons, although they resemble colorectal tumors in many respects. The purpose of this study was to determine whether abnormalities in the expression of several cell cycle control genes are of importance in small bowel tumorigenesis by comparing a series of samples of normal mucosa, adenomatous polyps, and adenocarcinomas. The levels of cyclin D1, cyclin E, p16, p21, p27, and p53 proteins were determined by immunohistochemistry in samples of normal small bowel (n = 16), small bowel adenomas (n = 20), and small bowel adenocarcinomas (n = 24). Normal small bowel mucosa expressed p27 protein, but not the other cell cycle-related proteins. About 20% of the tumors displayed a decrease in the expression of this protein. The most frequent alteration in the tumors was an increase in the p16 protein. Increased expression of p53 was associated with tumor progression because it was overexpressed in 45% of the adenomas and 65% of the adenocarcinomas (P<0.05). Advanced age and increased detection of cyclin D1 and p53 were associated with a decreased 3-year survival (P<0.05). Cell cycle abnormalities are early and important events in the multistep process of small bowel tumorigenesis, thus resembling colorectal carcinogenesis. As in colon cancer, deregulated expression of G1 proteins may perturb cell cycle control in benign adenomas of the small bowel and thereby enhance tumor progression. Increased expression of cell cycle inhibitors in tumors may serve as a defense mechanism for tumor progression.

Adenocarcinoma↗

PubMed1998

Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas.

To determine the status of chromosome 10q23 in primary breast carcinomas, in situ and invasive carcinomas were analysed for allelic loss using microsatellite markers spanning the 10q23 region. No LOH was seen in pure intraductal carcinomas (0/20 cases). On the other hand, LOH was observed in 40% (17/42) of invasive carcinomas (P = 0.0005). Interestingly, in situ lesions found in invasive tumors displayed LOH. Allelic loss was also significantly associated with loss of the estrogen receptor (P = 0.011). Thus, loss of the 10q23 is strongly associated with tumor progression.

Breast Neoplasms↗

PubMed1997

PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.

Amino Acid Sequence↗

PubMed1997

Convenient, nonradioactive, heteroduplex-based methods for identifying recurrent mutations in the BRCA1 and BRCA2 genes.

The ability to identify individuals who are predisposed to specific malignant tumors is a promising molecular diagnostic by-product of over two decades of intensive research into the genetic pathogenesis of human cancer. Approximately 2% of Ashkenazi Jews carry recurrent germline mutations in either the BRCA1 or BRCA2 genes that may predispose these individuals to the development of breast and ovarian cancer. We have developed a nonisotopic method, based on the formation of heteroduplexes between polymerase chain reaction (PCR) amplified wild-type and mutant alleles, which can be used to identify the BRCA1 185delAG and the BRCA2 6174delT mutations. The same assay can also be used to verify the loss of heterozygosity in a tumor sample arising in an individual with a germline mutation. The four steps described in this report (PCR amplification, heteroduplex formation, acrylamide gel electrophoresis, and ethidium bromide staining/UV-fluorescence photography) can be readily and reproducibly performed in the course of a single day, making this a useful method for the routine identification of these mutations.

Alleles↗

PubMed1997

Immunohistochemical and molecular genetic approaches to soft tissue tumor diagnosis: a primer.

During the past two decades we have witnessed the identification of an expanding list of immunohistochemical and molecular markers linked to histopathologically defined subtypes of tumors. These markers offer new insights and approaches to the classification of tumors with important prognostic and/or therapeutic implications. We review the potentially diagnostic immunohistochemical and molecular markers of soft tissue tumors (STTs). The immunohistochemical markers reviewed include vimentin, cytokeratin, desmin, HHF35, S100, myoD1, alpha1-antitrypsin, vascular markers (factor VIII, CD31, CD34), MIC2, and others. The potentially diagnostic chromosomal translocations and associated genes identified in STT include Ewing's/PNET t(11;22)(q24;q12)(FLI1;EWS), t(21;22)(q22;q12)(ERG; EWS); t(7;22)(p22;q12)(ETV1;EWS); desmoplastic small round cell tumor t(11;22)(p13;q12)(WT1;EWS); extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) (TEC(CHN);EWS); malignant ectomesenchymoma t(11;22)(q24;q12)(FLI1;EWS); alveolar rhabdomyosarcoma t(2;13)(q35;q14)(PAX-3;FKHR); t(1;13) (p36;q14)(PAX-7;FKHR); myxoid and round cell liposarcoma t(12;16)(q13;p11)(CHOP;TLS(FUS)); synovial sarcoma t(X;18)(p11;q11)(SSX1&2;SYT), and others. The nature, utility, and limitations of these markers in diagnostic settings are explored.

Biomarkers, Tumor↗