Detection of human papillomavirus DNA and p53 codon 72 polymorphism in prostate carcinomas of patients from Argentina

BACKGROUND: Infections with high-risk human papillomaviruses (HPVs), causatively linked to cervical cancer, might also play a role in the development of prostate cancer. Furthermore, the polymorphism at codon 72 (encoding either arginine or proline) of the p53 tumor-suppressor gene is discussed as a possible determinant for cancer risk. The HPV E6 oncoprotein induces degradation of the p53 protein. The aim of this study was to analyse prostate carcinomas and hyperplasias of patients from Argentina for the presence of HPV DNA and the p53 codon 72 polymorphism genotype. METHODS: HPV DNA detection and typing were done by consensus L1 and type-specific PCR assays, respectively, and Southern blot hybridizations. Genotyping of p53 codon 72 polymorphism was performed both by allele specific primer PCRs and PCR-RFLP (Bsh1236I). Fischer's test with Woolf's approximation was used for statistical analysis. RESULTS: HPV DNA was detected in 17 out of 41 (41.5 %) carcinoma samples, whereas all 30 hyperplasia samples were HPV-negative. Differences in p53 codon 72 allelic frequencies were not observed, neither between carcinomas and hyperplasias nor between HPV-positive and HPV-negative carcinomas. CONCLUSION: These results indicate that the p53 genotype is probably not a risk factor for prostate cancer, and that HPV infections could be associated with at least a subset of prostate carcinomas

HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can behave as a tumor suppressor, by pushing the cells towards epithelial differentiation.Landspitali University Hospital Science Fund, University of Iceland Research Fund, Science and Technology Policy Council Research Fund and Grant of Excellence, ‘Göngum saman’, a supporting group for breast cancer research in Iceland

Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype

Background: Dicer, a ribonuclease, is the key enzyme required for the biogenesis of microRNAs and small interfering RNAs and is essential for both mammalian development and cell differentiation. Recent evidence indicates that Dicer may also be involved in tumourigenesis. However, no studies have examined the clinical significance of Dicer at both the RNA and the protein levels in breast cancer.Methods: In this study, the biological and prognostic value of Dicer expression was assessed in breast cancer cell lines, breast cancer progression cellular models, and in two well-characterised sets of breast carcinoma samples obtained from patients with long-term follow-up using tissue microarrays and quantitative reverse transcription-PCR.Results: We have found that Dicer protein expression is significantly associated with hormone receptor status and cancer subtype in breast tumours (ER P=0.008; PR P=0.019; cancer subtype P=0.023, luminal A P=0.0174). Dicer mRNA expression appeared to have an independent prognostic impact in metastatic disease (hazard ratio=3.36, P=0.0032). In the breast cancer cell lines, lower Dicer expression was found in cells harbouring a mesenchymal phenotype and in metastatic bone derivatives of a breast cancer cell line. These findings suggest that the downregulation of Dicer expression may be related to the metastatic spread of tumours.Conclusion: Assessment of Dicer expression may facilitate prediction of distant metastases for patients suffering from breast cancer

Polymorphisme génétique d'une sérine protéase

LYON1-BU Santé (693882101) / SudocSudocFranceF

Elaboration et évaluation de fiches informatives sur des protocoles de chimiothérapie

LYON1-BU Santé (693882101) / SudocSudocFranceF

Instabilité génétique et cancer du sein (implication de Dicer, enzyme-clé du mécanisme d'ARN interférence dans la réponse au stress génotoxique)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Dicer, Enzyme clef de l'interférence ARN (études de son intérêt dans les cancers du sein et implication dans la réponse au stress réplicatif)

Breast cancers are the first cause of mortality in occidental women population. Breast tumours can show various forms which are frequently resistant to therapeutics and prone to late relapse. Thus, the current clinical challenge consists in refining individual therapeutics management by employing tools provided by the study of molecular basis of mammary tumorigenesis. Besides, chromosomal instability (CIN) is a hallmark of breast cancer and recent data showed that Dicer, a key ribonuclease of the RNA interference mechanism, could be a regulator of chromosomal stability in human cells. We thus hypothesized that alteration of this protein could be associated with mammary tumorigenesis. In order to test this hypothesis, we assessed dicer transcription and expression in breast cancer cell lines and tissues corresponding to different phases of tumor progression. We further investigated the consequences of dicer knock-down on cell cycle and response to replicative stress. Our results show that dicer expression has an independent prognostic value for metastatic relapse prediction and is correlated with hormonal receptors expression. Furthermore, cells harbouring dicer inactivation presented defects in cell cycle and DNA breaks response pathways. Altogether, our data indicate that dicer inactivation could favour CIN during mammary tumorigenesis and this feature could represent a useful tool in breast cancer managementLes cancers du sein sont la première cause de mortalité chez les femmes occidentales. Ils présentent une grande hétérogénéité associée à une résistance aux traitements et un taux de rechute important. Ainsi, les cliniciens doivent personnaliser la prise en charge des patientes et ce par une meilleure connaissance des causes moléculaires qui participent à l apparition et à la progression des tumeurs mammaires. Pour ce projet, nous avons choisi d étudier les éventuelles valeurs pronostique et diagnostique de dicer, gène clef du mécanisme d interférence ARN. Il a été montré une implication de Dicer dans la mise en place de l hétérochromatine de novo des péricentromeres. Les données disponibles nous ont permis d envisager que Dicer pourrait être impliquée dans la régulation de la stabilité chromosomique. Nous avons donc testé les valeurs pronostique et diagnostique de dicer (en PCR quantitative et en Tissue Microarray) dans une centaine d échantillons de tumeurs, dans des lignées et modèles cellulaires. Parallèlement, nous avons étudié les conséquences d une inhibition de l expression de dicer sur le cycle cellulaire et sur la réponse à un stress réplicatif. Nos résultats ont montré que l expression de dicer est un facteur pronostique indépendant de rechutes métastatiques. Par ailleurs, les cellules n exprimant pas dicer ont montré des dérégulations du cycle cellulaire et de la voie de réponse aux cassures de l ADN. En conclusion, l altération de l expression de dicer pourrait jouer un rôle dans l apparition de l instabilité chromosomique des cancers du sein et son analyse pourrait permettre une meilleure prise en charge des patientes à risque pour une rechute métastatique.LYON1-BU.Sciences (692662101) / SudocSudocFranceF