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1. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness.

Author

Sáez-Freire, María Del Mar, Blanco-Gómez, Adrián, Castillo-Lluva, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, María Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, Jesús

Abstract

The data presented in this article are related to the research paper entitled "The biological age linked to oxidative stress modifies breast cancer aggressiveness" (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. García-Criado, M.C. Patino-Alonso, P. Galindo-Villardón, J.H. Mao, C. Prieto, A. Castellanos-Martín, L. Kaderali, J. Pérez-Losada). The data shown were obtained from a population of transgenic mice, MMTV-Erbb2/Neu, with different susceptibility to breast cancer and a mixed genetic background generated by backcrossing. It was observed that the aggressiveness of breast cancer negatively correlates with age, being lower in chronologically old mice, similar to what occurs in humans. Given that oxidative stress is associated with tumour susceptibility and the degree of aging, the association between the aggressiveness of breast cancer and multiple intermediate phenotypes directly or indirectly related to oxidative stress was studied. Using a mathematical model, we defined biological age and the degree of aging as the difference between biological and chronological ages. As a result, we observed that biologically old mice predominated among those that developed the disease early on, that is, those that were chronologically young. We then identified the specific and common genetic components of Quantitative Trait loci or QTL associated with different evolution of breast cancer, the intermediate phenotypes related to oxidative stress studied, the biological age and the degree of aging. Lastly, we showed that the expression pattern in the livers of biologically old mice were enriched in signalling pathways related to inflammation and response to infections; whereas the biologically young mice exhibited enriched pathways related to mitochondrial activity. For the explanation and discussion of these data refer to the research article cited above.

Published
2018

2. The biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Sáez-Freire, María Del Mar, Blanco-Gómez, Adrián, Castillo-Lluva, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, María Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, Jesús

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Breast Cancer, Liver Disease, Genetics, Cancer, Aging, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Animals, Breast Neoplasms, Female, Genes, erbB-2, Glutathione, Inflammation, Liver, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Theoretical, Oxidative Stress, Proto-Oncogene Proteins c-akt, Quantitative Trait Loci, Receptor, ErbB-2, Transcriptome, Breast cancer, Biological age, Mouse genetics, Oxidative stress, Subphenotypes, Receptor, erbB-2, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.

Published
2018

3. Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression

Author

Blanco-Gómez, Adrián, Hontecillas-Prieto, Roberto Corchado-Cobos, Natalia García-Sancha, Nélida Salvador, Andrés Castellanos-Martín, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, Alonso-López, Diego, Castillo Lluva, Sonia, Javier De Las Rivas, Mar Lorente, Ana García-Casas, Sofía Del Carmen, Abad-Hernández, María del Mar, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Claros-Ampuero, Juncal, García-Cenador, Begoña, García-Criado, Javier, Akira Orimo, Thomas Gridley, Pérez-Losada, Jesús, Blanco-Gómez, Adrián, Hontecillas-Prieto, Roberto Corchado-Cobos, Natalia García-Sancha, Nélida Salvador, Andrés Castellanos-Martín, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, Alonso-López, Diego, Castillo Lluva, Sonia, Javier De Las Rivas, Mar Lorente, Ana García-Casas, Sofía Del Carmen, Abad-Hernández, María del Mar, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Claros-Ampuero, Juncal, García-Cenador, Begoña, García-Criado, Javier, Akira Orimo, Thomas Gridley, and Pérez-Losada, Jesús

Abstract

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis., Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

Published
2024

4. Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach.

Author

Castellanos-Martín, Andrés, Castillo-Lluva, Sonia, Sáez-Freire, María Del Mar, Blanco-Gómez, Adrián, Hontecillas-Prieto, Lourdes, Patino-Alonso, Carmen, Galindo-Villardon, Purificación, Pérez Del Villar, Luis, Martín-Seisdedos, Carmen, Isidoro-Garcia, María, Abad-Hernández, María Del Mar, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, González-Sarmiento, Rogelio, Alonso-López, Diego, De Las Rivas, Javier, García-Cenador, Begoña, García-Criado, Javier, Lee, Do Yup, Bowen, Benjamin, Reindl, Wolfgang, Northen, Trent, Mao, Jian-Hua, and Pérez-Losada, Jesús

Subjects
Animals, Humans, Mice, Breast Neoplasms, Neoplasm Metastasis, Disease Progression, Receptor, erbB-2, Systems Biology, MAP Kinase Signaling System, Gene Expression Regulation, Neoplastic, Models, Genetic, Female, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Receptor, erbB-2, Gene Expression Regulation, Neoplastic, Models, Genetic, ErbB-2, Breast Cancer, Cancer, Digestive Diseases, Genetics, 2.1 Biological and endogenous factors, Bioinformatics, Environmental Sciences, Biological Sciences, Information and Computing Sciences
Abstract

BackgroundAn essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels.ResultsHere, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease.ConclusionsConsidering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

Published
2015

5. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Gómez-Vecino, Aurora, primary, Corchado-Cobos, Roberto, additional, Blanco-Gómez, Adrián, additional, García-Sancha, Natalia, additional, Castillo-Lluva, Sonia, additional, Martín-García, Ana, additional, Mendiburu-Eliçabe, Marina, additional, Prieto, Carlos, additional, Ruiz-Pinto, Sara, additional, Pita, Guillermo, additional, Velasco-Ruiz, Alejandro, additional, Patino-Alonso, Carmen, additional, Galindo-Villardón, Purificación, additional, Vera-Pedrosa, María Linarejos, additional, Jalife, José, additional, Mao, Jian-Hua, additional, Macías de Plasencia, Guillermo, additional, Castellanos-Martín, Andrés, additional, Sáez-Freire, María del Mar, additional, Fraile-Martín, Susana, additional, Rodrigues-Teixeira, Telmo, additional, García-Macías, Carmen, additional, Galvis-Jiménez, Julie Milena, additional, García-Sánchez, Asunción, additional, Isidoro-García, María, additional, Fuentes, Manuel, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, García-Hernández, Juan Luis, additional, Hernández-García, María Ángeles, additional, Cruz-Hernández, Juan Jesús, additional, Rodríguez-Sánchez, César Augusto, additional, García-Sancho, Alejandro Martín, additional, Pérez-López, Estefanía, additional, Pérez-Martínez, Antonio, additional, Gutiérrez-Larraya, Federico, additional, Cartón, Antonio J., additional, García-Sáenz, José Ángel, additional, Patiño-García, Ana, additional, Martín, Miguel, additional, Alonso-Gordoa, Teresa, additional, Vulsteke, Christof, additional, Croes, Lieselot, additional, Hatse, Sigrid, additional, Van Brussel, Thomas, additional, Lambrechts, Diether, additional, Wildiers, Hans, additional, Hang, Chang, additional, Holgado-Madruga, Marina, additional, González-Neira, Anna, additional, Sánchez, Pedro L., additional, and Pérez Losada, Jesús, additional

Published
2023
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6. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Gómez Vecino, Aurora, Corchado Cobos, Roberto, Blanco Gómez, Adrián, García Sancha, Natalia, Martín García, Ana, Mendiburu-Eliçabe Garganta, Marina, Prieto, Carlos, Ruiz Pinto, Sara, Pita, Guillermo, Velasco Ruiz, Alejandro, Patino Alonso, Carmen, Galindo Villardón, Purificación, Linarejos Vera Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Fraile Martín, Susana, Rodrigues Teixeira, Telmo, García Macías, Carmen, Galvis Jiménez, Julie Milena, Castillo Lluva, Sonia, García Sánchez, Asunción, Isidoro García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Hang, Chang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., Pérez Losada, Jesús, Gómez Vecino, Aurora, Corchado Cobos, Roberto, Blanco Gómez, Adrián, García Sancha, Natalia, Martín García, Ana, Mendiburu-Eliçabe Garganta, Marina, Prieto, Carlos, Ruiz Pinto, Sara, Pita, Guillermo, Velasco Ruiz, Alejandro, Patino Alonso, Carmen, Galindo Villardón, Purificación, Linarejos Vera Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Fraile Martín, Susana, Rodrigues Teixeira, Telmo, García Macías, Carmen, Galvis Jiménez, Julie Milena, Castillo Lluva, Sonia, García Sánchez, Asunción, Isidoro García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín García-Sancho, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Hang, Chang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., and Pérez Losada, Jesús

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management., Ministerio de Ciencia, Innovación y Universidades (España), European Comission, Junta de Castilla y León, Instituto de Salud Carlos III, Ministerio de Economía, Comercio y Empresa (España), Federación Española de Enfermedades Raras, Departamento de Defensa (Estados Unidos), National Institutes of Health (Estados Unidos), Universidad de California (Estados Unidos), Instituto Nacional del Cáncer (Estados Unidos), Fundación "la Caixa", Agencia Estatal de Investigación, Depto. de Estadística e Investigación Operativa, Fac. de Farmacia, TRUE, pub

Published
2023

7. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Instituto de Salud Carlos III, Department of Defense (US), National Institutes of Health (US), National Cancer Institute (US), Lawrence Berkeley National Laboratory, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martin-Garcia, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile, Susana, Rodrigues Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Hernández-García, María Ángeles, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, M., González-Neira, Anna, Sánchez, Pedro L, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Junta de Castilla y León, Instituto de Salud Carlos III, Department of Defense (US), National Institutes of Health (US), National Cancer Institute (US), Lawrence Berkeley National Laboratory, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martin-Garcia, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile, Susana, Rodrigues Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Hernández-García, María Ángeles, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, M., González-Neira, Anna, Sánchez, Pedro L, and Pérez-Losada, J.

Abstract

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Published
2023

8. Supplementary Data from Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression

Author

Blanco-Gómez, Adrián, primary, Hontecillas-Prieto, Lourdes, primary, Corchado-Cobos, Roberto, primary, García-Sancha, Natalia, primary, Salvador, Nélida, primary, Castellanos-Martín, Andrés, primary, Sáez-Freire, María del Mar, primary, Mendiburu-Eliçabe, Marina, primary, Alonso-López, Diego, primary, De Las Rivas, Javier, primary, Lorente, Mar, primary, García-Casas, Ana, primary, Del Carmen, Sofía, primary, Abad-Hernández, María del Mar, primary, Cruz-Hernández, Juan Jesús, primary, Rodríguez-Sánchez, César Augusto, primary, Claros-Ampuero, Juncal, primary, García-Cenador, Begoña, primary, García-Criado, Javier, primary, Orimo, Akira, primary, Gridley, Thomas, primary, Pérez-Losada, Jesús, primary, and Castillo-Lluva, Sonia, primary

Published
2023
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9. Datasets related to a study aimed to identify genetic markers of CDA by subphenotypes associated with cardiotoxicity

Author

European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Pérez-Losada, J. [0000-0003-2400-624X], Macías de Plasencia, Guillermo, Fraile, Susana, Rodrigues Teixeira, Telmo, Hernández-García, María Ángeles, Holgado-Madruga, M., González-Neira, Ana, Sánchez, Pedro L., Pérez-Losada, J., Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, Castillo, Sonia, García-Sancha, Natalia, Martin-Garcia, Ana, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín-Ruiz, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Saenz, José Ángel, Patiño-García, Ana, Martin, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Martín, Miguel A., European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Fundación la Caixa, Centro Nacional de Investigaciones Cardiovasculares (España), Pérez-Losada, J. [0000-0003-2400-624X], Macías de Plasencia, Guillermo, Fraile, Susana, Rodrigues Teixeira, Telmo, Hernández-García, María Ángeles, Holgado-Madruga, M., González-Neira, Ana, Sánchez, Pedro L., Pérez-Losada, J., Gómez-Vecino, Aurora, Corchado Cobos, Roberto, Blanco-Gómez, Adrián, Castillo, Sonia, García-Sancha, Natalia, Martin-Garcia, Ana, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Linarejos Vera-Pedrosa, María, Jalife, José, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, Begoña, García-Criado, Francisco Javier, García, Juan L., Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Martín-Ruiz, Alejandro, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J., García-Saenz, José Ángel, Patiño-García, Ana, Martin, Miguel, Alonso Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, and Martín, Miguel A.

Abstract

Here we present a series of supplemental datasets that complement our study entitled "A Systems Genetics approach to identify genetic markers of cardiotoxicity due to anthracyclines in cancer patients." The datasets presented here were used to generate the main and supplementary figures and tables of the indicated study. The study consists of the identification of genetic markers of cardiotoxicity due to anthracyclines (CDA). CDA is a complex genesis disease or complex trait, and because of this, there is a component of missing heritability. Therefore, it is not possible to identify genetic markers associated with CDA risk. Here, we propose that molecular subphenotypes associated with the CDA may be a strategy for identifying some of this missing heritability and risk markers associated with it. A similar strategy could be applied to identify markers of other diseases of complex genesis. This study is done using a genetically heterogeneous cohort of mice that developed breast cancer and was treated with doxorubicin or a combined treatment of doxorubicin and docetaxel. The mouse cohort was generated by backcrossing, so each mouse is genetically unique. Post-chemotherapy heart damage was assessed by quantifying fibrosis's cardiac area and the thickness of myocardial fibers. The genetic regions associated with CDA were assessed by massive genotyping and genetic linkage analysis. Several molecular subphenotypes were quantified in the myocardium, and their association with the CDA was evaluated. Subsequently, we identified which of them were most statistically associated with CDA in multivariate models. Moreover, which complex trait loci (QTLs) associated with molecular subphenotypes best explained CDA. This strategy served to identify in the cohort of mice genes whose allelic forms could be candidates for the risk of CDA. Allelic variants of these genes were evaluated in four cohorts of cancer patients treated with anthracyclines and whose CDA was evaluated by echocardi

Published
2021

10. Stromal SNAI2 is required for ERBB2 breast cancer progression

Author

Blanco Gómez, Adrián, Hontecillas Prieto, Lourdes, Corchado Cobos, Roberto, García Sancha, Natalia, Salvador Tormo, Nélida, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Mendiburu-Eliçabe Garganta, Marina, Alonso López, Diego, De Las Rivas Sanz, Javier, Lorente Pérez, María Del Mar, García Casas, Ana, Del Carmen Martínez, Sofía, Abad Hernández, María del Mar, Cruz Hernández, Juan Jesús, Rodríguez Sánchez, César Augusto, Claros Ampuero, Juncal, García Cenador, Begoña, García Criado, Javier, Orimo, Akira, Gridley, Thomas, Pérez Losada, Jesús, Castillo Lluva, Sonia, Blanco Gómez, Adrián, Hontecillas Prieto, Lourdes, Corchado Cobos, Roberto, García Sancha, Natalia, Salvador Tormo, Nélida, Castellanos Martín, Andrés, Sáez Freire, María del Mar, Mendiburu-Eliçabe Garganta, Marina, Alonso López, Diego, De Las Rivas Sanz, Javier, Lorente Pérez, María Del Mar, García Casas, Ana, Del Carmen Martínez, Sofía, Abad Hernández, María del Mar, Cruz Hernández, Juan Jesús, Rodríguez Sánchez, César Augusto, Claros Ampuero, Juncal, García Cenador, Begoña, García Criado, Javier, Orimo, Akira, Gridley, Thomas, Pérez Losada, Jesús, and Castillo Lluva, Sonia

Abstract

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis., Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Castilla y León, National Institutes of Health, Sandra Ibarra Foundation for Solidarity against Cancer, “We can be heroes” Foundation, Federación Española de Enfermedades Raras, Sección Deptal. de Bioquímica y Biología Molecular (Biológicas), Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, Fac. de Ciencias Químicas, TRUE, pub

Published
2020

11. Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression

Author

Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), European Commission, Instituto de Salud Carlos III, Junta de Castilla y León, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, National Institutes of Health (US), Blanco-Gómez, Adrián, Hontecillas-Prieto, Lourdes, Corchado Cobos, Roberto, García-Sancha, Natalia, Salvador, Nélida, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, Alonso-López, D., Rivas, Javier de las, Lorente, Mar, García-Casas, Ana, Carmen, Sofía del, Abad-Hernández, María del Mar, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Claros-Ampuero, Juncal, García-Cenador, Begoña, García-Criado, Francisco Javier, Orimo, Akira, Gridley, Thomas, Pérez-Losada, J., Castillo, Sonia, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), European Commission, Instituto de Salud Carlos III, Junta de Castilla y León, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, National Institutes of Health (US), Blanco-Gómez, Adrián, Hontecillas-Prieto, Lourdes, Corchado Cobos, Roberto, García-Sancha, Natalia, Salvador, Nélida, Castellanos-Martín, Andrés, Sáez-Freire, María del Mar, Mendiburu-Eliçabe, Marina, Alonso-López, D., Rivas, Javier de las, Lorente, Mar, García-Casas, Ana, Carmen, Sofía del, Abad-Hernández, María del Mar, Cruz, Juan Jesús, Rodríguez-Sánchez, César Augusto, Claros-Ampuero, Juncal, García-Cenador, Begoña, García-Criado, Francisco Javier, Orimo, Akira, Gridley, Thomas, Pérez-Losada, J., and Castillo, Sonia

Abstract

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis.

Published
2020

12. Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression

Author

Blanco-Gómez, Adrián, primary, Hontecillas-Prieto, Lourdes, additional, Corchado-Cobos, Roberto, additional, García-Sancha, Natalia, additional, Salvador, Nélida, additional, Castellanos-Martín, Andrés, additional, Sáez-Freire, María del Mar, additional, Mendiburu-Eliçabe, Marina, additional, Alonso-López, Diego, additional, De Las Rivas, Javier, additional, Lorente, Mar, additional, García-Casas, Ana, additional, Del Carmen, Sofía, additional, Abad-Hernández, María del Mar, additional, Cruz-Hernández, Juan Jesús, additional, Rodríguez-Sánchez, César Augusto, additional, Claros-Ampuero, Juncal, additional, García-Cenador, Begoña, additional, García-Criado, Javier, additional, Orimo, Akira, additional, Gridley, Thomas, additional, Pérez-Losada, Jesús, additional, and Castillo-Lluva, Sonia, additional

Published
2020
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13. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Ministerio de Ciencia e Innovación (España), National Cancer Institute (US), Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Department of Energy (US), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), National Cancer Institute (US), Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Department of Energy (US), Instituto de Salud Carlos III, European Commission, National Institutes of Health (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, J.

Abstract

The data presented in this article are related to the research paper entitled “The biological age linked to oxidative stress modifies breast cancer aggressiveness” (M.M. Sáez-Freire, A. Blanco-Gómez, S. Castillo-Lluva, A. Gómez-Vecino, J.M. Galvis-Jiménez, C. Martín-Seisdedos, M. Isidoro-García, L. Hontecillas-Prieto, M.B. García-Cenador, F.J. García-Criado, M.C. Patino-Alonso, P. Galindo-Villardón, J.H. Mao, C. Prieto, A. Castellanos-Martín, L. Kaderali, J. Pérez-Losada). The data shown were obtained from a population of transgenic mice, MMTV-Erbb2/Neu, with different susceptibility to breast cancer and a mixed genetic background generated by backcrossing. It was observed that the aggressiveness of breast cancer negatively correlates with age, being lower in chronologically old mice, similar to what occurs in humans. Given that oxidative stress is associated with tumour susceptibility and the degree of aging, the association between the aggressiveness of breast cancer and multiple intermediate phenotypes directly or indirectly related to oxidative stress was studied. Using a mathematical model, we defined biological age and the degree of aging as the difference between biological and chronological ages. As a result, we observed that biologically old mice predominated among those that developed the disease early on, that is, those that were chronologically young. We then identified the specific and common genetic components of Quantitative Trait loci or QTL associated with different evolution of breast cancer, the intermediate phenotypes related to oxidative stress studied, the biological age and the degree of aging. Lastly, we showed that the expression pattern in the livers of biologically old mice were enriched in signalling pathways related to inflammation and response to infections; whereas the biologically young mice exhibited enriched pathways related to mitochondrial activity. For the explanation and discussion of these data refer to the research article cit

Published
2018

14. The biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, National Institutes of Health (US), National Cancer Institute (US), Department of Energy (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, Pérez-Losada, J., Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, National Institutes of Health (US), National Cancer Institute (US), Department of Energy (US), Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Castillo, Sonia, Gómez-Vecino, Aurora, Galvis-Jiménez, Julie Milena, Martín-Seisdedos, Carmen, Isidoro-García, María, Hontecillas-Prieto, Lourdes, García-Cenador, Begoña, García-Criado, Francisco Javier, Patino-Alonso, María Carmen, Galindo-Villardón, Purificación, Mao, Jian-Hua, Prieto, Carlos, Castellanos-Martín, Andrés, Kaderali, Lars, and Pérez-Losada, J.

Abstract

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.

Published
2018

15. Supplementary data for the biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Sáez-Freire, María del Mar, primary, Blanco-Gómez, Adrián, additional, Castillo-Lluva, Sonia, additional, Gómez-Vecino, Aurora, additional, Galvis-Jiménez, Julie Milena, additional, Martín-Seisdedos, Carmen, additional, Isidoro-García, María, additional, Hontecillas-Prieto, Lourdes, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, Patino-Alonso, María Carmen, additional, Galindo-Villardón, Purificación, additional, Mao, Jian-Hua, additional, Prieto, Carlos, additional, Castellanos-Martín, Andrés, additional, Kaderali, Lars, additional, and Pérez-Losada, Jesús, additional

Published
2018
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16. The biological age linked to oxidative stress modifies breast cancer aggressiveness

Author

Sáez-Freire, María del Mar, primary, Blanco-Gómez, Adrián, additional, Castillo-Lluva, Sonia, additional, Gómez-Vecino, Aurora, additional, Galvis-Jiménez, Julie Milena, additional, Martín-Seisdedos, Carmen, additional, Isidoro-García, María, additional, Hontecillas-Prieto, Lourdes, additional, García-Cenador, María Begoña, additional, García-Criado, Francisco Javier, additional, Patino-Alonso, María Carmen, additional, Galindo-Villardón, Purificación, additional, Mao, Jian-Hua, additional, Prieto, Carlos, additional, Castellanos-Martín, Andrés, additional, Kaderali, Lars, additional, and Pérez-Losada, Jesús, additional

Published
2018
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17. Resumen de tesis. Identificación de determinantes moleculares y genéticos comunes a la susceptibilidad del cáncer de mama y al envejecimiento mediante una estrategia de biología de sistemas

Author

Sáez Freire, María del Mar, Pérez Losada, Jesús, and Muñoz Bermejo, María Eugenia

Subjects
Oncology, Resumen de tesis, Thesis Abstracts, Universidad de Salamanca (España), Tesis y disertaciones académicas, Envejecimiento de la población, Oncología
Abstract

[ES] INTRODUCCIÓN Entre los factores epidemiológicos que modifican el riesgo de desarrollar cáncer de mama y su variabilidad de presentación clínico-fenotípica, la edad es uno de los más importantes. La influencia de la edad tiene una doble vertiente, por un lado se observa un aumento de la incidencia de cáncer de mama con la edad; por otro, su desarrollo en pacientes jóvenes con frecuencia se asocia con una mayor agresividad y peor pronóstico. El cáncer y el grado de envejecimiento son procesos denominados de génesis compleja, y están influenciados por la interacción entre factores ambientales y un componente de herencia poligénica. En la génesis de ambos, cáncer y el envejecimiento, participan múltiples fenotipos intermedios, algunos de ellos comunes a ambos, como son los fenotipos relacionados con el estrés oxidativo HIPÓTESIS Y OBJETIVO Nuestra hipótesis de trabajo fue que la variabilidad fenotípica que presenta el cáncer de mama con la edad se podría explicar, al menos en parte: (i) por el distinto comportamiento con la edad de las vías de señalización intratumorales debajo del receptor ERBB2 y (ii) por la relación patogénica que existe entre el cáncer de mama y el envejecimiento, sobre todo a través de fenotipos intermedios de estrés oxidativo. Nuestro objetivo principal fue identificar marcadores o determinantes moleculares y genéticos asociados al distinto comportamiento del cáncer de mama en susceptibilidad y evolución en función de la edad. METODOLOGÍA Para ello, generamos una cohorte de ratones con distinta susceptibilidad y evolución del cáncer de mama, mediante un retrocruce, cruzando dos cepas, una resistente y otra susceptible al desarrollo de cáncer de mama (C57BL/6 y FVB, respectivamente), la última portadora del pro-oncogén MMTV-ErbB2/Neu. Diseccionamos la enfermedad en distintos patofenotipos, como la latencia tumoral, parámetros de progresión local, número de tumores, desarrollo de metástasis, duración de la enfermedad y supervivencia. En esos mismos ratones, se determinaron fenotipos relacionados con el estrés oxidativo, como agentes pro-oxidantes, antioxidantes y biomarcadores de daño celular. Se llevaron a cabo estudios de ligamiento para identificar los QTL asociados con cada uno de los fenotipos analizados. RESULTADOS (i) Identificamos la heterogeneidad fenotípica en susceptibilidad y evolución del cáncer de mama ERBB2-positivo en función de la edad cronológica, en una población de ratones de variabilidad genética controlada. (ii) Observamos que la variabilidad con la edad en los niveles de algunas de las vías de señalización intratumorales activadas por el receptor ERBB2, se asoció con la heterogeneidad fenotípica en susceptibilidad y evolución del cáncer de mama. (iii) Encontramos asociación entre los fenotipos intermedios relacionados con el estrés oxidativo y la evolución del cáncer de mama ERBB2-positivo. (iv) Identificamos regiones genómicas de rasgo cuantitativo o complejo (QTL) asociadas a la susceptibilidad y evolución del cáncer de mama, a la señalización intratumoral y a los fenotipos intermedios de estrés oxidativo estudiados. (v) Aplicamos modelos de análisis multivariante para pronosticar el comportamiento del cáncer de mama en función de los fenotipos intermedios de estrés oxidativo y las regiones QTL identificadas. (vi) Utilizamos modelos multivariantes para integrar la información de los fenotipos de estrés oxidativo y los marcadores genéticos y definir la edad biológica de cada ratón. Así, identificamos los ratones biológicamente más jóvenes y viejos de lo que les correspondería para su edad cronológica (incremento de edad biológica), y analizamos las características clínico-patológicas de los mismos. Aquellos animales que desarrollaron la enfermedad muy tarde demostraron ser biológicamente más jóvenes de lo que les correspondía para su edad, mientras que los ratones que desarrollaron el tumor a edades tempranas, fueron biológicamente más viejos que sus equivalentes en edad cronológica y sin tumor. Identificamos también regiones genómicas de rasgo cuantitativo (QTL) asociadas con el incremento de la edad biológica. Dichas regiones se asociaron simultáneamente con la variabilidad de algunos de los patofenotipos del cáncer de mama. CONCLUSIONES Hemos identificado un conjunto de marcadores genéticos y moleculares que han permitido definir la heterogeneidad de la presentación del cáncer de mama ERBB2-positivo, en relación con la edad, para lo que hemos considerado una serie de fenotipos intermedios de estrés oxidativo que participan en la patogenia del cáncer y del envejecimiento.

Published
2016

18. Analysis of genetics determinants intrinsic to the tumor cells related to the heterogenous response to chemotherapy in a mouse model of ERBB2 breast cancer

Author

Blanco-Gómez, Adrián, Sáez-Freire, María del Mar, Castillo, Sonia, Hontecillas-Prieto, Lourdes, Hernández Mulas, M. Luz, García-Cenador, Begoña, García-Criado, Francisco Javier, Mao, Jian-Hua, Galindo-Villardón, Purificación, Castellanos-Martín, Andrés, and Pérez-Losada, J.

Abstract

Resumen del trabajo presentado a la EACR-OECI Conference: "Precision Medicine for Cancer", celebrada en Neumünster Abbey (Luxemburgo) del 1 al 4 de marzo de 2015.-- et al., An essential aspect of breast cancer is its different evolution among patients with the same histopathological disease. Moreover, cancer is a tissue growing in the context of a complex organism, thus it can be identified two main sources of variability responsible for the disease behavior: intrinsic and extrinsic factors which act, respectively, mainly inside the tumor cells and outside them at local or systemic levels. Our aim is to identify intrinsic factors to the tumor cells responsible for the different responses of breast cancer to chemotherapy with Doxorubicin and Docetaxel. For this purpose, we collected tumors developed in a cohort of genetically heterogeneous mice from a backcross between a resistant strain to breast cáncer (C57BL/6) and a susceptible one (FVB) which overexpress the cNeu/ErbB2 protooncogene controlled by the MMTV prometer. The backcross mice were genotyped by SNP analysis. To identify tumor intrinsic factors controlling the response to chemotherapy, we transplanted 125 tumors collected from the backcross mice into singenic F1-C57/FVB mice to remove variability coming from the host compartments. Each tumor was transplanted into two F1 reciplent mice; each one was treated with Doxorubicin or Docetaxel, and we studied tumor response to treatment. Linkage analysis permits us to identify QTL (Quantitative Trait Loci) controlling susceptibility to mammary cancer and evolution of the disease in the backcross population, and the specific intrinsic QTL associated with different chemotherapy responses in the F1 mice. Moreover, we are studying molecular and signalling pathways that control chemotherapy responses and the QTL associated with them. The identification of breast cancer susceptibility genes and their pathways associated with different response to chemotherapy will be important for the prediction of human breast cancer evolution during therapy, and to learn about the mechanisms involved in resistance to chemotherapy, thus it would help to develop new preventivo and therapeutic strategies.

Published
2015

19. Strategy for the identification of the tumor intrinsic QTL determining the response to treatment of ERBB2 breast cancer

Author

Blanco-Gómez, Adrián, Sáez-Freire, María del Mar, Castillo, Sonia, Hontecillas-Prieto, Lourdes, Hernández Mulas, M. Luz, García-Cenador, Begoña, García-Criado, Francisco Javier, Mao, Jian-Hua, Galindo-Villardón, Purificación, Castellanos-Martín, Andrés, and Pérez-Losada, J.

Abstract

Resumen del póster presentado al VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas, celebrado en el Centro de Investigación del Cáncer (CIC-IBMCC) del 21 al 22 de mayo de 2015.-- et al., Este póster ha ganado el 1er premio en el Concurso de Pósters de Oncología Básica y Traslacional en Oncología para Jóvenes Investigadores, celebrado durante el VII Simposium Bases Biológicas del Cáncer y Terapias Personalizadas., An essential aspect of breast cancer is its different evolution among patients with the same histopathological disease. Moreover, cancer is a tissue growing in the context of a complex organism, thus it can be identified two main sources of variability responsible for the disease behavior: intrinsic and extrinsic factors which act, respectively, mainly inside the tumor cells and outside them at local or systemic levels. Our aim is to identify intrinsic factors to the tumor cells responsible for the different responses of breast cancer to chemotherapy with Doxorubicin and Docetaxel. For this purpose, we collected tumors developed in a cohort of genetically heterogeneous mice from a backcross between a resistant strain to breast cancer (C57BL/6) and a susceptible one (FVB) which overexpress the cNeu/ErbB2 protooncogene controlled by the MMTV promoter. The backcross mice were genotyped by SNP analysis. To identify tumor intrinsic factors controlling the response to chemotherapy, we transplanted 125 tumors collected from the backcross mice into singenic F1-C57/FVB mice to remove variability coming from the host compartments. Each tumor was transplanted into two F1 recipient mice; each one was treated with Doxorubicin or Docetaxel, and we studied tumor response to treatment. Linkage analysis permits us to identify QTL (Quantitative Trait Loci) controlling susceptibility to mammary cancer and evolution of the disease in the backcross population, and the specific intrinsic QTL associated with different chemotherapy responses in the F1 mice. Moreover, we are studying molecular and signalling pathways that control chemotherapy responses and the QTL associated with them. The identification of breast cancer susceptibility genes and their pathways associated with different response to chemotherapy will be important for the prediction of human breast cancer evolution during therapy, and to learn about the mechanisms involved in resistance to chemotherapy, thus it would help to develop new preventive and therapeutic strategies.

Published
2015

20. Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes

Author

Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Obra Social Kutxa, Fundación Eugenio Rodríguez Pascual, Junta de Castilla y León, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Department of Energy (US), National Institutes of Health (US), National Cancer Institute (US), Blanco-Gómez, Adrián, Castillo, Sonia, Sáez-Freire, María del Mar, Hontecillas-Prieto, Lourdes, Mao, Jian-Hua, Castellanos-Martín, Andrés, Pérez-Losada, J., Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Obra Social Kutxa, Fundación Eugenio Rodríguez Pascual, Junta de Castilla y León, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Department of Energy (US), National Institutes of Health (US), National Cancer Institute (US), Blanco-Gómez, Adrián, Castillo, Sonia, Sáez-Freire, María del Mar, Hontecillas-Prieto, Lourdes, Mao, Jian-Hua, Castellanos-Martín, Andrés, and Pérez-Losada, J.

Abstract

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases.

Published
2016

21. Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

Author

Junta de Castilla y León, Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), Consejo Superior de Investigaciones Científicas (España), National Cancer Institute (US), Fundación Eugenio Rodríguez Pascual, Department of Energy (US), Federación Española de Enfermedades Raras, Obra Social Kutxa, German Research Foundation, Instituto de Salud Carlos III, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Castellanos-Martín, Andrés, Castillo, Sonia, Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Hontecillas-Prieto, Lourdes, Galindo-Villardón, Purificación, Pérez del Villar, Luis, Abad, María del Mar, Cruz, Juan Jesús, González-Sarmiento, Rogelio, De Las Rivas, Javier, García-Cenador, Begoña, García-Criado, Francisco Javier, Northen, Trent, Mao, Jian-Hua, Pérez-Losada, J., Junta de Castilla y León, Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), Consejo Superior de Investigaciones Científicas (España), National Cancer Institute (US), Fundación Eugenio Rodríguez Pascual, Department of Energy (US), Federación Española de Enfermedades Raras, Obra Social Kutxa, German Research Foundation, Instituto de Salud Carlos III, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Castellanos-Martín, Andrés, Castillo, Sonia, Sáez-Freire, María del Mar, Blanco-Gómez, Adrián, Hontecillas-Prieto, Lourdes, Galindo-Villardón, Purificación, Pérez del Villar, Luis, Abad, María del Mar, Cruz, Juan Jesús, González-Sarmiento, Rogelio, De Las Rivas, Javier, García-Cenador, Begoña, García-Criado, Francisco Javier, Northen, Trent, Mao, Jian-Hua, and Pérez-Losada, J.

Abstract

[Background]: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. [Results]: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. [Conclusions]: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

Published
2015

22. A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

Author

National Cancer Institute (US), Department of Energy (US), National Institutes of Health (US), Ministerio de Ciencia e Innovación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Obra Social Kutxa, Junta de Castilla y León, Fundación Eugenio Rodríguez Pascual, Castillo, Sonia, Hontecillas-Prieto, Lourdes, Blanco-Gómez, Adrián, Sáez-Freire, María del Mar, García-Cenador, Begoña, García-Criado, Francisco Javier, Pérez-Andrés, Martin, Orfao, Alberto, Cañamero, Marta, Mao, Jian-Hua, Gridley, Thomas, Castellanos-Martín, Andrés, Pérez-Losada, J., National Cancer Institute (US), Department of Energy (US), National Institutes of Health (US), Ministerio de Ciencia e Innovación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Instituto de Salud Carlos III, Fundación Sandra Ibarra - Solidaridad Frente al Cáncer, Obra Social Kutxa, Junta de Castilla y León, Fundación Eugenio Rodríguez Pascual, Castillo, Sonia, Hontecillas-Prieto, Lourdes, Blanco-Gómez, Adrián, Sáez-Freire, María del Mar, García-Cenador, Begoña, García-Criado, Francisco Javier, Pérez-Andrés, Martin, Orfao, Alberto, Cañamero, Marta, Mao, Jian-Hua, Gridley, Thomas, Castellanos-Martín, Andrés, and Pérez-Losada, J.

Abstract

Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects - latency and tumor load - were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

Published
2015

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