Biomedical subjects

Ivan Bieche

Publications and source records attributed to Ivan Bieche.

11 recordsLinked to original sources

PubMed2005

Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy.

Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN) and AMN with cerebral demyelination (AMN-C) are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD). It is caused by mutations in the ABCD1 gene encoding a half-size peroxisomal transporter that has to dimerize to become functional. The biochemical hallmark of ALD is the accumulation of very-long-chain fatty acids (VLCFA) in plasma and tissues. However, there is no correlation between the ALD phenotype and the ABCD1 gene mutations or the accumulation of VLCFA in plasma and fibroblast from ALD patients. The absence of genotype-phenotype correlation suggests the existence of modifier genes. To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes. This study shows that: (1) ABCD1 gene mutations leading to truncated ALD protein are unlikely to cause variation in the ALD phenotype; (2) accumulation of saturated VLCFA in normal-appearing WM correlates with ALD phenotype and (3) expression of the ABCD4 and BG1, but not of the ABCD2, ABCD3 and VLCS genes, tends to be correlated with the severity of the disease, acting early in the pathogenesis of ALD.

ATP-Binding Cassette Transporters↗

PubMed2005

Update on inflammatory breast cancer.

Inflammatory breast cancer (IBC) is both the least frequent and the most severe form of epithelial breast cancer. The diagnosis is based on clinical inflammatory signs and is reinforced by pathological findings. Significant progress has been made in the management of IBC in the past 20 years. Yet survival among IBC patients is still only one-half that among patients with non-IBC. Identification of the molecular determinants of IBC would probably lead to more specific treatments and to improved survival. In the present article we review recent advances in the molecular pathogenesis of IBC. A more comprehensive view will probably be obtained by pan-genomic analysis of human IBC samples, and by functional in vitro and in vivo assays. These approaches may offer better patient outcome in the near future.

Animals↗

PubMed2004

RASSF4/AD037 is a potential ras effector/tumor suppressor of the RASSF family.

Activated Ras proteins interact with a broad range of effector proteins to induce a diverse series of biological consequences. Although typically associated with enhanced growth and transformation, activated Ras may also induce growth antagonistic effects such as senescence or apoptosis. It is now apparent that some of the growth-inhibitory properties of Ras are mediated via the RASSF family of Ras effector/tumor suppressors. To date, four members of this family have been identified (Nore1, RASSF1, RASSF2, and RASSF3). We now identify a fifth member of this group, RASSF4 (AD037). RASSF4 shows approximately 25% identity with RASSF1A and 60% identity with RASSF2. RASSF4 binds directly to activated K-Ras in a GTP-dependent manner via the effector domain, thus exhibiting the basic properties of a Ras effector. Overexpression of RASSF4 induces Ras-dependent apoptosis in 293-T cells and inhibits the growth of human tumor cell lines. Although broadly expressed in normal tissue, RASSF4 is frequently down-regulated by promoter methylation in human tumor cells. Thus, RASSF4 appears to be a new member of the RASSF family of potential Ras effector/tumor suppressors.

Amino Acid Sequence↗

PubMed2004

Evaluation of mRNA expression of estrogen receptor beta and its isoforms in human normal and neoplastic endometrium.

Endometrial cancer is well known to be estrogen-dependent. Two estrogen receptor types, ERalpha and ERbeta, are major mediators of a diversity of biologic functions of estrogen and play an important role in estrogen-dependent tissues and cancers. Cloning of ERbeta was followed by the discovery of a variety of its isoforms. Using real-time RT-PCR, the relative expression levels of ERbeta1, ERbeta2 (ERbetacx), ERbeta3, ERbeta4 and ERbeta5 were studied. We observed coexpression of ERbeta isoforms in the endometrium and upregulation of the ERbeta5 transcript in malignant endometrium. We also observed downregulation of ERbeta2Delta5 transcript in neoplastic endometrium, using a semiquantitative method. Our results suggest that analyzing the changes in ERbeta and its isoforms may be important in the diagnosis, prognosis and treatment of endometrial cancer.

Adenocarcinoma↗

PubMed2004

Molecular profiling of benign prostatic hyperplasia using a large scale real-time reverse transcriptase-polymerase chain reaction approach.

PURPOSE: Benign prostatic hyperplasia (BPH) is characterized by a hyperplastic growth of epithelial and stromal cells in the prostate. Despite the high prevalence of the disease little is known regarding the molecular etiology of BPH. Therefore, a comparison of gene expression patterns between normal prostate, BPH and prostate cancer could provide insights into the pathogenic mechanisms of the disease and identify candidate genes that could be targeted for therapeutic use. MATERIALS AND METHODS: Prostate tissue specimen were obtained from 30 patients undergoing adenomectomy for BPH. Adenoma weight was less than 60 gm in 15 patients and more than 60 gm in the remainder. Normal prostate tissue was obtained from 15 patients undergoing radical prostatectomy for cancer from areas selected for absent tumor and BPH. Two pools of organ confined prostate cancer were also analyzed. We quantified in the 5 pools of tissues the expression of 327 genes using real-time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: A total of 23 genes showed increased expression in BPH with a fold change of at least 2.5 between normal prostate and the 2 BPH groups, of which most were normal or down-regulated in prostate cancer. Seven genes showed decreased expression in BPH with a fold change of at least 3.5 between normal prostate and BPH. Most of them were also normal or down-regulated in prostate cancer. CONCLUSIONS: We identified a set of genes up-regulated in BPH compared to normal prostate tissue and often prostate cancer, including genes previously implicated in BPH and others not previously linked to this disease to our knowledge. Further investigations are now warranted to determine the clinical relevance and therapeutic potential of these genes.

Aged↗

PubMed2003

Two prognostic groups of inflammatory breast cancer have distinct genotypes.

PURPOSE: The prognosis of inflammatory breast cancer (IBC) remains poor despite the use of multimodality treatments, with a 10-year survival rate of not >30%. Clinicopathological and biological predictors of outcome are inadequate in this setting. Analysis of loss of heterozygosity (LOH) can provide a molecular portrait of the genetic alterations underlying stepwise cancer progression. We tested the value of LOH patterns as diagnostic and prognostic markers in IBC. EXPERIMENTAL DESIGN: In a previous study of 64 patients with IBC who were treated homogeneously between 1988 and 1999, we determined LOH frequencies at 71 loci located in 20 chromosomal regions associated with primary breast cancer. Six of these regions bore alterations that were less frequent in non-IBC. In the present study, we sought correlations between these molecular data and the clinicopathological features and clinical outcome of the same 64 patients. RESULTS: With the exception of stage IV disease, extensive breast inflammation at first clinical examination was the main factor associated with poor outcome (P = 0.00065 versus localized inflammation). The overall frequency of LOH was also higher in this group (P = 0.000073). LOH patterns differed between patients with localized and extensive breast inflammation. CONCLUSION: Patients with IBC can be separated into two major prognostic groups on the basis of initial clinical signs, which appear to be subtended by different molecular alterations.

Adult↗

PubMed2003

[Detection of telomerase activity by semi-quantitative and in situ assays and quantification of hTERT expression in bladder carcinomas].

OBJECTIVES: Several studies have reported the important role played by telomerase, an enzyme which maintains the length of telomeres, during carcinogenesis. The objective of this study was to detect telomerase activity by semiquantitative in situ methods and to quantify expression of the hTERT subunit in a group of bladder cancers in order to assess its diagnostic and prognostic value. MATERIAL AND METHODS: Telomerase activity (TA) was detected by the TRAP method ("telomeric repeat amplification protocol") on a series of 29 bladder cancers and 3 samples of healthy mucosa. Levels of expression of the hTERT gene were studied by real-time quantitative RT-PCR. In situ detection of TA was performed by using the same kit as the TRAP method, applied to frozen tissue sections exclusively for cases with discordant results between TA detection and hTERT mRNA. RESULTS: TA was detected by TRAP in 15 of the 29 bladder cancers. hTERT mRNA was detected and quantified in all tumour samples. A significant correlation was observed between TA and the level of hTERT mRNA expression. In situ detection of TA demonstrated heterogeneous TA in tumour tissue. A significant correlation was observed between the level of hTERT mRNA expression and tumour histological grades and stages. CONCLUSION: hTERT mRNA detection by real-time quantitative RT-PCR appears to be a sensitive method for the diagnosis of bladder cancer with a good correlation with tumour grade and stage. Quantitative evaluation of hTERT mRNA could therefore be a useful marker of tumour progression for the early diagnosis and follow-up of bladder cancers.

DNA-Binding Proteins↗

PubMed2002

Evidence of chromosome regions and gene involvement in inflammatory breast cancer.

Inflammatory breast cancer (IBC) is a rare but particularly aggressive form of primary breast cancer. In contrast to noninflammatory breast cancer (non IBC), the molecular alterations underlying IBC are poorly known. We postulated that the kind and frequency of these alterations might differ between IBC and non IBC and account for its particular aggressiveness. We investigated allelic losses associated with primary breast cancer (on chromosome arms 1p, 3p, 6p, 6q, 7q, 8p, 9p, 11p, 11q, 16q, 17p and 17q) by analyzing 71 microsatellite markers in 66 cases of IBC. Loss of heterozygosity (LOH) was frequent, with a mean fractional allelic loss (FAL) index of 52%. Relative to published data on non IBC, allelic loss was particularly frequent at 3p21-p14, 6p, 8p22, 11q, 13q14 and 17q21, suggesting the presence of genes that are markedly altered in IBC. In contrast, the DNA amplification levels of ERBB2, MYC and CCND1, as measured by real-time quantitative PCR, did not differ between IBC and non IBC.

Breast Neoplasms↗

PubMed2002

SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers.

Slit2 plays a vital role in axon guidance by signaling through Robo receptors. Recent evidence suggests that Slit2 protein may function in other settings because human and Xenopus Slit2 has been shown to inhibit leukocyte chemotaxis. SLIT2 protein is a putative ligand for the ROBO receptors. We recently demonstrated that ROBO1 is inactivated by promoter region hypermethylation in <20% of human cancers; furthermore, tumor suppressor activity has not been shown. Thus, the importance of ROBO1 inactivation in human cancer is uncertain. Therefore, we investigated the status of SLIT2 located at 4p15.2 in lung and breast cancers. Although somatic SLIT2 mutations were not detected, epigenetic inactivation was common. SLIT2 promoter methylation was detected in 59% of breast cancer, 77% of non-small cell lung cancer, and 55% of small cell lung cancer cell lines. In these tumor lines, SLIT2 expression was restored by treatment with a demethylating agent. SLIT2 promoter methylation was detected in 43% of breast cancer, 53% of non-small cell lung cancer, and 36% of small cell lung cancer primary tumors. The majority of methylated tumors demonstrated allelic loss at 4p15.2. In addition, SLIT2 expression was down-regulated in methylated breast tumors, relative to normal control, as demonstrated by quantitative real-time reverse transcription-PCR. Overexpression of SLIT2 suppressed >70% of colony growth in each of three breast tumor lines (with either absent or low SLIT2 expression). Because SLIT2 is primarily a secreted protein, SLIT2-conditioned medium suppressed the growth of several breast cancer lines (with absent or weak SLIT2expression) by 26-51% but had no significant effect on a breast tumor cell line that expresses normal levels of SLIT2. These findings demonstrate that SLIT2 is frequently inactivated in lung and breast cancer by promoter region hypermethylation and allele loss and is an excellent candidate for the lung and breast tumor suppressor gene previously mapped to 4p15.2.

Animals↗

PubMed2002

Genetic pathways in the evolution of breast ductal carcinoma in situ.

The patterns of allelic loss in 28 cases of pure ductal carcinoma in situ (DCIS) and 25 cases of DCIS associated with invasive ductal carcinoma (IDC) were compared, in order to define whether pure DCIS represented an earlier stage than DCIS associated with IDC in the progression of breast carcinoma. To this aim, the polymerase chain reaction (PCR) was performed on microdissected normal and neoplastic breast tissue, formalin-fixed and paraffin-embedded. Fifteen microsatellite markers were examined, on chromosomes 1p, 3p, 7q, 11q, 12p, 13q, 16q and 17q, mostly focused on regions altered in breast cancer. Loss of heterozygosity (LOH) was greater in pure DCIS than in the DCIS component associated with IDC for 11 out of 15 markers. The difference was statistically significant for D13S260 and D17S800 (p=0.008 and p=0.01, respectively). DCIS associated with IDC showed a lesser degree of alteration than the synchronous IDC component for ten out of 15 markers. In contrast, LOH at D11S1816 and D16S318 was lower in pure DCIS than in DCIS associated with IDC and even greater in the IDC component. These results confirm that DCIS is a possible but not an obligate precursor of invasive breast cancer and suggest that pure DCIS and DCIS associated with IDC may be genetically distinct. The evolution from DCIS to IDC may follow multiple pathways and not a linear model.

Breast Neoplasms↗

PubMedDate not supplied

Prognostic value of uPA, PAI-1 and PAI-2 mRNA expression in primary breast cancer.

BACKGROUND: The prognostic value of uPA, PAI-1 and PAI-2 mRNA expression was studied in a retrospective series of 130 primary breast cancer patients (median follow-up 8.1 years). MATERIALS AND METHODS: UPA, PAI-1 and PAI-2 mRNA were quantified by means of real-time quantitative RT-PCR. Comparison with the corresponding protein levels determined by ELISA was performed in 21 cases. RESULTS: Higher uPA protein values were found in cases with high mRNA values, but the relationship was of borderline significance. PAI-1 and PAI-2 mRNA were positively correlated to protein values. The mRNA expression of uPA, PAI-1 and PAI-2 was significantly correlated with one another. Higher uPA and PAI-1 mRNA values were significantly associated with shorter disease-free survival (DFS) (p = 0.002; p = 0.03, respectively). Low and very high PAI-2 mRNA values tended to be associated with longer DFS. In Cox multivariate analyses, higher uPA and PAI-1 mRNA values were independently associated with shorter DFS. PAI-2 was not retained as a significant variable in the Cox model. CONCLUSION: These preliminary results indicate that, in breast cancer, uPA, PAI-1 and PAI-2 mRNA analysis by quantitative RT-PCR give results comparable to those obtained at the protein level.

Breast Neoplasms↗