Our lab is interested to understand the molecular mechanisms of carcinogensinduced by environmental and dietary exposures (e.g. occupational exposure and chemotherapeutic agents, (e.g. personalized treatment for breast cancer), taking advances of the molecular biology of disease (e.g. cell cycle disturbance by endogenous and exogenous carcinogens, metabolism of carcinogens, DNA repair, andapoptosis) and new methodologies (e.g. Sequencing technologies – the next generation), in order to estimate the accurate role of DNA lesion and genetic susceptibility in Human chronic pathologies.
Carcinogens, DNA lesion damage and repair in aging and cancer: A Toxicogenetics approach.
Aging is a multidimensional process, usually with gradual onset, which results from the effects of genetic and environmental interactions, whose understanding is crucial for unravelling the mechanisms of longevity and aging related diseases. The health of an individual depends upon their DNA as well as upon environment factors (exposome). The exposome represents all toxicants to which people are exposed from both exogenous and endogenous sources and needs to be characterized in order to understand environmental causes of aging and disease.
Since aging is a complex physiological process that poses many problems and conundrums to rapidly aging societies, there is also an urgent need for readily accessible and reproducible biological markers of aging and cancer, by the use of new methodologies/ technologies. These results should be correlated with individual’s genome fingerprint, having as final intention the correlation of this exposome/genome relation with aging and breast cancer.
Familial breast cancer: new biomarkers for an early diagnosis/prognosis
Breast cancer (BC) belongs to the most frequent cancer types in women worldwide. The golden standard method for early diagnosis is still mammography despite its low specificity.
The need for better biomarkers for early BC diagnosis and prognosis is undoubtedly necessary. Knowing the importance of gene environment interactions (GxE) related with cancer, studies of these GxE interactions are needed to obtain better estimates of population-attributable risk(s). The group aims to identify reliable biomarkers of familial breast cancer (FBC) using an exposome top-down study evaluating the internal exposure and early biological effects in a group of women through data on metabolic phenotype, microRNA (miRNA) related with BC, candidate gene variations, oxidative status, DNA repair capacity and susceptibility to FBC.
Additionally, we are also interested in the use of Gold nano-particles, in the development of a more specific and highly sensitive biomolecular diagnostic platform, taking advantage of the high specificity and informative use of microRNAs, using a potential non-invasive methodologies (urine samples) in diagnosis/prognosis of breast cancer.
Breast cancer chemotherapeutic agents: DNA repair polymorphisms, drug response and biomarkers.
Compromised DNA repair is an impetus for carcinogenesis and might promote aggressive clinical behaviour in breast cancer. The different response to chemotherapeutic treatment is subject to wide interindividual variability, which is expressed, not only as differences in severity and type of toxicity, but also as differences in effectiveness. It is well known that several drugs used as breast cancer chemotherapeutic agents have as target the DNA molecule, inducing lesions that lead to neoplasic cell death. However, lesions caused by these agents (generally themselves genotoxic) require complex repair mechanisms.
The heterogeneity of patients’ genetic background allow to establish new strategies which to improve the breast cancer disease outcome to therapy increasing survival rate. In such way, would be relevant emphasize that the understanding of how genetics influence the patients cellular response to drugs, will make it easier to develop personalized therapeutic strategies.
Running as PI:
• “Biomarkers of dietary acrylamide exposure: human toxicological relevance”. PTDC/SAU-OSM/105572/2008.
• “Detecção de aductos de DNA em populações expostas a cancerígenos ambientais recorrendo a nanossondas de ouro coloidal.” Fundação Calouste Gulbenkian. Projeto nº 76436, abril 2006 a março de 2009.
• “Lesão genética induzida pela acrilamida: Qual a sua relevância em cancerigénese mamária, tiroideia e do sistema nervoso central?” Fundação Calouste Gulbenkian. Projeto nº 76438, fevereiro de 2006 a janeiro de 2009.
• “Susceptibilidade genética para cancro da mama”. Fundação Calouste Gulbenkian. Projeto nº 69405, dezembro de 2004 a novembro de 2007. In collaboration with José Rueff, FCM-UNL.
• “Identificação de factores de risco para tumores primários do sistema nervoso central”. Fundação Calouste Gulbenkian. Projeto nº 69407, dezembro de 2004 a novembro de 2007.
Running as Collaborator (2004-2017)
• Terry Fox Grant 2017. Liga Portuguesa Contra o Cancro. “Breast Cancer: clinical significance of variants of unknown significance (VUSs) in homologous recombination repair genes – from sequencing to functional analysis in familial breast cancer patients”
• “The usefulness of serologic infection markers in Pneumocystis jirovecii pneumonia (PcP): A new diagnostic approach.” CMDT-LA, PI Francisco Esteves, IHMT-UNL, January-December 2012.
• “Clinical relevance of multiple genetic markers in Pneumocystis jirovecii pneumonia (PcP): New high-throughput methodologies for molecular epidemiology and diagnosis.” PTDC/SAU-MIC/116716/2010. PI: Olga Matos, IHMT-UNL. Started in January 2010.
• “GenFA – Occupational Exposure to Formaldehyde. Genotoxic Damage and Susceptibility evaluation in Pathology Anatomy Laboratory workers”. PTDC/SAU-ESA/102367/2008. PI: João Paulo Teixeira, INSA. Started: April 2010.
• “The Role of β-glucan in Pneumocystis jiroverii Pneumonia (PcP): A new diagnostic tool.” PTDC/SAU-MII/104231/2008. PI: Olga Matos, IHMT-UNL. Started: January 2010.
• “Novel bioorganometallic SERM analogues – synthesis and evaluation of anti-cancer potential”. PTDC/QUI/67522/2006.
• “Medicinal plants from Angola: biological activity”. PTDC/QUI/66507/2006. PI: Dina Malheiros Mendonça, UBI.
• “SHIPs: Sat-based Haplotype Inference by Pure Parsimony”. PTDC/EIA/64164/2006. PI: Inês Lynce Faria. INESC, IST-UTL.
• “Nanodiagnostics: gold-nanoprobes for molecular recognition – application to DNA adducts detection; pathogen detection; gene expression and RNA quantification”. PTDC/SAU-BEB/66511/2006. PI: Pedro Viana Baptista. FFCT-UNL.
• “Sensitive and selective detection of DNA/RNA based on functionalised gold nanoparticles – application to pathogen detection; mutation detection and RNA quantification”. PTDC/BIO/66514/2006. PI: Pedro Viana Baptista. FFCT-UNL.
• “Lead exposure. Contribution for the study of genetic and imunologic toxicity. Influence of genetic determinants”. PDCT/SAL-OBS/59821/2004.
• “Breast cancer: Evaluation of the role of environmental and food carcinogens in its initiation”. POCTI/QUI/57110/2004. PI: Gonçalo Gamboa, IST-UTL. 2004-2007.
Chapters in international books:
C.Martins, J.Rueff, A.S.Rodrigues
“HANDBOOK OF FOODBORNE DISEASES”
Food Microbiology series
Taylor and Francis CRC Press (2017, ‘in press’)
AS.Rodrigues, BC.Gomes, C.Martins, M.Gromicho, NG.Oliveira, PS.Guerreiro, J.Rueff.
DNA Repair and Resistance to Cancer Therapy.
In C. Chen (Ed.) “New Research Directions in DNA Repair”, ISBN: 978-953-51-1114-6; pp 489-528. InTech ( 2013)
SN. Silva, BC. Gomes, J. Rueff, JF. Gaspar.
DNA Repair perspectives in Thyroid and Breast cancer: the role of DNA repair polymorphisms.
in Vengrova S. (Ed.) “DNA Repair and Human Health”. ISBN: 978-953-307-612-6; pp: 439-484. InTech (2011).
O. Anunciacão, BC. Gomes, S. Vinga, J. Gaspar, AL. Oliveira, J. Rueff.
A Data Mining Approach for the detection of High-Risk Breast Cancer Groups.
in: Miguel Rocha,P., Fernandez Riverola F., Shatkay. H., Corchado J.M. (Eds.). in “Advances in Bioinformatics (4th International Workshop on Practical Applications of Computational Biology and Bioinformatics 2010 (IWPACBB 2010)”. pp: 43-52. Springer-Verlag Berlin Heidelberg, Germany. (2010).
M. Monteiro, A. S. Rodrigues, A. Vicente, J. Murias, C. Martins, J. Rueff, H. Borba, Medimond: Potassium bromate oxidative DNA damage in repair proficient and deficient CHO cell lines. 01/2007: pages 93-97; , ISBN: 9788875874032 (2007)
Medeiros MG, Rodrigues AS, Batoréu MCC,Laires A, Rueff J, Zhitkovich A.
Biomarkers of Chromium Exposure and Cytogenetic damage.
in “Leather Tanning and Welding Industry Workers”. Plenum Press; New York. 01/2003; (2003)
J. Rueff, J. Gaspar, A. Laires.
Human exposure to nitroso compounds: Identification, mechanisms of genetic lesion and individual genetic susceptibility.
In: Burdinola: “Encouraging scientific research: 10 years of Burdinola’s Scientific Research Award” . pp: 237-274. (2002)
Gaspar, I. Duarte Silva, A. Laires, A. Rodrigues, S. Costa, J. Rueff.
Prooxidant activities of flavonols: a structure activity study.
in: Kumpulainen J.T. and Salonen J.T. (eds), Natural Antioxidants and Lipid Peroxidation in Atherosclerosis and Cancer. pp: 291-297.The Royal Society of Chemistry, Cambridge, UK. (1996).
Rodrigues AS, Silva ID, Monteiro MJ, Caria H, Laires A, Chaveca T, Rueff J.
ACTIVATION OF PROMUTAGENS BY RAT CYP P450 EXPRESSING V79 CELLS. 01/1994: pages 205-208; , ISBN: 274200050X (1994)
J. Rueff, A. Laires, A. Brás, H. Borba, T. Chaveca, J. Gaspar, A. Rodrigues, L. Cristóvão e M. Monteiro.
DNA damage and oxygen Species.
in Lambert M. (ed), “DNA Repair Mechanisms and their Biological Implications in Mammalian Cells” pp.171-181. Plenum Press, New York. (1989).
Papers in peer-reviewed international publications:
Azevedo PA, Silva SN, De Lima JP, Reichert A, Lima F, Júnior E, Rueff J.
DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms.
ONCOLOGY LETTERS. 2017; 13: 4641-4650
D’ Oliveira Martins F, Gomes BC, Rodrigues AS, Rueff J
Genetic Susceptibility in Acute Pancreatitis: Genotyping of GSTM1, GSTT1, GSTP1,
CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, and TP53 Gene Variants.
Pancreas. 2017; 46(1):71-76
Rueff J, Rodrigues AS.
Methods Mol Biol. 2016;1395:v-vii.
Gonçalves J, Moreira E, Sequeira IJ, Rodrigues AS, Rueff J, Brás A.
Integration of HIV in the Human Genome: Which Sites Are Preferential? A Genetic and Statistical Assessment.
Int J Genomics. 2016; 2016:2168590.
de Lima JP, Silva SN, Rueff J, Pingarilho M. Glycidamide genotoxicity
modulated by Caspases genes polymorphisms. Toxicol In Vitro. 2016; ;34:123-127.
Brito Palma B, Fisher CW, Rueff J, Kranendonk M.
Prototype Systems Containing Human Cytochrome P450 for High-Throughput Real-Time Detection of DNA Damage by Compounds That Form DNA-Reactive Metabolites.
Chem Res Toxicol. 2016 ;
Gomes BC, Santos B, Rueff J, Rodrigues AS.
Methods for Studying MicroRNA Expression and Their Targets in Formalin-Fixed, Paraffin-Embedded (FFPE) Breast Cancer Tissues.
Methods Mol Biol. 2016; 1395:189-205.
Gomes BC, Rueff J, Rodrigues AS.
MicroRNAs and Cancer Drug Resistance.
Methods Mol Biol. 2016; 1395:137-162.
Rueff J, Rodrigues AS.
Cancer Drug Resistance: A Brief Overview from a Genetic Viewpoint.
Methods Mol Biol. 2016;1 395:1-18.
Kranendonk M, Alves M, Antunes P, Rueff J. Human sulfotransferase
1A1-dependent mutagenicity of 12-hydroxy-nevirapine: the missing link?
Chem Res Toxicol. 2014 ; 17;27(11):1967-1971.
Martins C, Doran C, Silva IC, Miranda C, Rueff J, Rodrigues AS.
Myristicin from nutmeg induces apoptosis via the mitochondrial pathway and down regulates genes of the DNA damage response pathways in human leukaemia K562 cells.
Chem Biol Interact. 2014 ;25:1-9.
Bandarra S, Fernandes AS, Magro I, Guerreiro PS, Pingarilho M, Churchwell MI, Gil OM, Batinic-Haberle I, Gonçalves S, Rueff J, Miranda JP, Marques MM, Beland
FA, Castro M, Gaspar JF, Oliveira NG.
Mechanistic insights into the cytotoxicity and genotoxicity induced by glycidamide in human mammary cells.
Mutagenesis. 2013;28(6):721-729. Erratum in: Mutagenesis. 2014; Jan;29(1):97.
Palma BB, Silva E Sousa M, Urban P, Rueff J, Kranendonk M. Functional
characterization of eight human CYP1A2 variants: the role of cytochrome b5.
Pharmacogenet Genomics. 2013 ;23(2):41-52. .
Gromicho M, Magalhães M, Torres F, Dinis J, Fernandes AR, Rendeiro P, Tavares P, Laires A, Rueff J, Sebastião Rodrigues A.
Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib.
Oncol Rep. 2013 ;29(2):741-750.
• Dr. Frederick Beland, National Center for Toxicological Research, Arkansas USA.
• Blanca Laffon. Department of Psychology, University of A Coruña.
• Prof. Doutora Matilde Marques, Instituto Superior Técnico, Universidade Técnica de Lisboa.
• Prof. Doutora Olga Matos, Unidade de protozoários oportunistas do Instituto de Higiene e Medicina Tropical (UNL).
• Prof. Doutor João Paulo Teixeira, Departamento de Saúde Ocupacional, Instituto Nacional de Saúde Dr Ricardo Jorge, Porto.
• Prof. Doutor Pedro Baptista, Secção Autónoma de Biotecnologia da Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa.
• Prof. Doutor Nuno Oliveira. Faculdade de Farmácia da Universidade de Lisboa.
• Serviços de Patologia Clínica e de Cirurgia do Hospital de S. Francisco Xavier.