Person: Mendaza Lainez, Saioa
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Mendaza Lainez
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Saioa
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Ciencias de la Salud
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811567
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Publication Open Access CDH22 hypermethylation is an independent prognostic biomarker in breast cancer(BioMed Central, 2017) Martín Sánchez, Esperanza; Mendaza Lainez, Saioa; Ulazia Garmendia, Ane; Monreal Santesteban, Iñaki; Córdoba Iturriagagoitia, Alicia; Vicente García, Francisco; Blanco Luquin, Idoia; Cruz, Susana de la; Aramendia, Ana; Guerrero Setas, David; Ciencias de la Salud; Osasun ZientziakBackground: Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein involved in cell-cell adhesion and metastasis. Its role in cancer is controversial because it has been described as being upregulated in colorectal cancer, whereas it is downregulated in metastatic melanoma. However, its status in breast cancer (BC) is unknown. The purpose of our study was to determine the molecular status and clinical value of CDH22 in BC. Results: We observed by immunohistochemistry that the level of CDH22 expression was lower in BC tissues than in their matched adjacent-to-tumour and non-neoplastic tissues from reduction mammoplasties. Since epigenetic alteration is one of the main causes of gene silencing, we analysed the hypermethylation of 3 CpG sites in the CDH22 promoter by pyrosequencing in a series of 142 infiltrating duct BC cases. CDH22 was found to be hypermethylated in tumoral tissues relative to non-neoplastic mammary tissues. Importantly, this epigenetic alteration was already present in adjacent-to-tumour tissues, although to a lesser extent than in tumoral samples. Furthermore, CDH22 gene regulation was dynamically modulated in vitro by epigenetic drugs. Interestingly, CDH22 hypermethylation in all 3 CpG sites simultaneously, but not expression, was significantly associated with shorter progression-free survival (p = 0.015) and overall survival (p = 0.021) in our patient series. Importantly, CDH22 hypermethylation was an independent factor that predicts poor progression-free survival regardless of age and stage (p = 0.006). Conclusions: Our results are the first evidence that CDH22 is hypermethylated in BC and that this alteration is an independent prognostic factor in BC. Thus, CDH22 hypermethylation could be a potential biomarker of poor prognosis in BC.Publication Open Access ADAM12 is a potential therapeutic target regulated by hypomethylation in triple-negative breast cancer(MDPI, 2020) Mendaza Lainez, Saioa; Ulazia Garmendia, Ane; Monreal Santesteban, Iñaki; Córdoba Iturriagagoitia, Alicia; Ruiz de Azúa, Yerani; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate PublikoaTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and currently lacks any effective targeted therapy. Since epigenetic alterations are a common event in TNBC, DNA methylation profiling can be useful for identifying potential biomarkers and therapeutic targets. Here, genome-wide DNA methylation from eight TNBC and six non-neoplastic tissues was analysed using Illumina Human Methylation 450K BeadChip. Results were validated by pyrosequencing in an independent cohort of 50 TNBC and 24 non-neoplastic samples, where protein expression was also assessed by immunohistochemistry. The functional role of disintegrin and metalloproteinase domain-containing protein 12(ADAM12) in TNBC cell proliferation, migration and drug response was analysed by gene expression silencing with short hairpin RNA. Three genes (Von Willenbrand factor C and Epidermal Growth Factor domain-containing protein (VWCE), tetraspanin-9 (TSPAN9) and ADAM12) were found to be exclusively hypomethylated in TNBC. Furthermore, ADAM12 hypomethylation was associated with a worse outcome in TNBC tissues and was also found in adjacent-to-tumour tissue and, preliminarily, in plasma from TNBC patients. In addition, ADAM12 silencing decreased TNBC cell proliferation and migration and improved doxorubicin sensitivity in TNBC cells. Our results indicate that ADAM12 is a potential therapeutic target and its hypomethylation could be a poor outcome biomarker in TNBC.Publication Open Access A DNA methylation-based gene signature can predict triple-negative breast cancer diagnosis(MDPI, 2021) Mendaza Lainez, Saioa; Guerrero Setas, David; Monreal Santesteban, Iñaki; Ulazia Garmendia, Ane; Córdoba Iturriagagoitia, Alicia; Cruz, Susana de la; Martín Sánchez, Esperanza; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate PublikoaTriple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype and lacks targeted treatment. It is diagnosed by the absence of immunohistochemical expression of several biomarkers, but this method still displays some interlaboratory variability. DNA methylome aberrations are common in BC, thereby methylation profiling could provide the identification of accurate TNBC diagnosis biomarkers. Here, we generated a signature of differentially methylated probes with class prediction ability between 5 non-neoplastic breast and 7 TNBC tissues (error rate = 0.083). The robustness of this signature was corroborated in larger cohorts of additional 58 non-neoplastic breast, 93 TNBC, and 150 BC samples from the Gene Expression Omnibus repository, where it yielded an error rate of 0.006. Furthermore, we validated by pyrosequencing the hypo-methylation of three out of 34 selected probes (FLJ43663, PBX Homeobox 1 (PBX1), and RAS P21 protein activator 3 (RASA3) in 51 TNBC, even at early stages of the disease. Finally, we found significantly lower methylation levels of FLJ43663 in cell free-DNA from the plasma of six TNBC patients than in 15 healthy donors. In conclusion, we report a novel DNA methylation signature with potential predictive value for TNBC diagnosis.Publication Open Access CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer(Impact Journals, 2017) Martín Sánchez, Esperanza; Mendaza Lainez, Saioa; Ulazia Garmendia, Ane; Monreal Santesteban, Iñaki; Blanco Luquin, Idoia; Córdoba Iturriagagoitia, Alicia; Vicente García, Francisco; Pérez Janices, Noemi; Escors Murugarren, David; Megías, Diego; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako GobernuaThe CHL1 gene encodes a cell-adhesion molecule proposed as being a putative tumour-suppressor gene in breast cancer (BC). However, neither the underlying molecular mechanisms nor the clinical value of CHL1 downregulation in BC has been explored. The methylation status of three CpG sites in the CHL1 promoter was analysed by pyrosequencing in neoplastic biopsies from 142 patients with invasive BC and compared with that of non-neoplastic tissues. We found higher CHL1 methylation levels in breast tumours than in non-neoplastic tissues, either from mammoplasties or adjacent-to-tumour, which correlated with lower levels of protein expression in tumours measured by immunohistochemistry. A panel of five BC cell lines was treated with two epigenetic drugs, and restoration of CHL1 expression was observed, indicating in vitro dynamic epigenetic regulation. CHL1 was silenced by shRNA in immortalized but non-neoplastic mammary cells, and enhanced cell proliferation and migration, but not invasion, were found by real-time cell analysis. The prognostic value of CHL1 hypermethylation was assessed by the log-rank test and fitted in a Cox regression model. Importantly, CHL1 hypermethylation was very significantly associated with shorter progression-free survival in our BC patient series, independent of age and stage (p = 0.001). In conclusion, our results indicate that CHL1 is downregulated by hypermethylation and that this epigenetic alteration is an independent prognostic factor in BC.Publication Open Access Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix(MDPI, 2020) Mendaza Lainez, Saioa; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Zudaire, Tamara; Guarch, Rosa; Guerrero Setas, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua; Universidad Pública de Navarra / Nafarroako Unibertsitate PublikoaThe tumor-suppressor protein p16 is paradoxically overexpressed in cervical cancer (CC). Despite its potential as a biomarker, its clinical value and the reasons for its failure in tumor suppression remain unclear. Our purpose was to determine p16 clinical and biological significance in CC. p16 expression pattern was examined by immunohistochemistry in 78 CC cases (high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix –SCCCs). CC cell proliferation and invasion were monitored by real-time cell analysis and Transwell® invasion assay, respectively. Cytoplasmic p16 interactors were identified from immunoprecipitated extracts by liquid chromatography-tandem mass spectrometry, and colocalization was confirmed by double-immunofluorescence. We observed that SCCCs showed significantly more cytoplasmic than nuclear p16 expression than HSILs. Importantly, nuclear p16 absence significantly predicted poor outcome in SCCC patients irrespective of other clinical parameters. Moreover, we demonstrated that cytoplasmic p16 interacted with CDK4 and other unreported proteins, such as BANF1, AKAP8 and AGTRAP, which could sequester p16 to avoid nuclear translocation, and then, impair its anti-tumor function. Our results suggest that the absence of nuclear p16 could be a diagnostic biomarker between HSIL and SCCC, and an independent prognostic biomarker in SCCC; and explain why p16 overexpression fails to stop CC growth.Publication Open Access Approaching the epigenome of triple negative breast cancer to identify new biomarkers(2020) Mendaza Lainez, Saioa; Guerrero Setas, David; Martín Sánchez, Esperanza; Ciencias de la Salud; Osasun ZientziakEl cáncer de mama (CM) es la neoplasia más frecuente en todo el mundo y la primera causa de muerte por cáncer en mujeres. El cáncer de mama triple negativo (CMTN) representa el 10-20% de todos los CM diagnosticados y es el subgrupo más agresivo puesto que carece tratamiento dirigido. Por lo tanto, el descubrimiento de nuevos biomarcadores y dianas terapéuticas es necesario. Dado que las alteraciones epigenéticas están involucradas en la tumorigénesis, la caracterización de la metilación del DNA y la acetilación de histonas puede ser útil para la identificación de nuevas firmas potencialmente diagnósticas o pronósticas, así como alteraciones destinatarias de fármacos dirigidos. En la presente tesis, se caracterizó la metilación de DNA del genoma completo de 8 CMTN y seis tejidos mamarios no neoplásicos mediante Illumina Human Methylation 450K BeadChip. Estos datos se analizaron desde dos enfoques bioinformáticos diferentes. Concluimos que el patrón epigenético (metiloma de DNA y acetiloma de histonas) está alterado en CMTN respecto a tejido mamario no neoplásico. Así como que la hipometilación de ADAM12 y la acetilación de H4K5 son potenciales biomarcadores de peor pronóstico y que ADAM12 es una potencial diana terapéutica en CMTN. También sugerimos la utilidad diagnóstica de una nueva firma basada en metilación de DNA y las diferencias entre los genes regulados por la acetilación de H4K6ac según la naturaleza de las líneas (no neoplásicas o TNBC).