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Mendaza Lainez, Saioa

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https://academica-e.unavarra.es/handle/2454/49563

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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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2020 - 20214
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End date: 2021 Ɨ Start date: 2020 Ɨ

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Now showing 1 - 4 of 4
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    PublicationOpen Access
    Approaching the epigenome of triple negative breast cancer to identify new biomarkers
    (2020) Mendaza Lainez, Saioa; Guerrero Setas, David; Martƭn SƔnchez, Esperanza; Ciencias de la Salud; Osasun Zientziak
    El cĆ”ncer de mama (CM) es la neoplasia mĆ”s frecuente en todo el mundo y la primera causa de muerte por cĆ”ncer en mujeres. El cĆ”ncer de mama triple negativo (CMTN) representa el 10-20% de todos los CM diagnosticados y es el subgrupo mĆ”s agresivo puesto que carece tratamiento dirigido. Por lo tanto, el descubrimiento de nuevos biomarcadores y dianas terapĆ©uticas es necesario. Dado que las alteraciones epigenĆ©ticas estĆ”n involucradas en la tumorigĆ©nesis, la caracterizaciĆ³n de la metilaciĆ³n del DNA y la acetilaciĆ³n de histonas puede ser Ćŗtil para la identificaciĆ³n de nuevas firmas potencialmente diagnĆ³sticas o pronĆ³sticas, asĆ­ como alteraciones destinatarias de fĆ”rmacos dirigidos. En la presente tesis, se caracterizĆ³ la metilaciĆ³n de DNA del genoma completo de 8 CMTN y seis tejidos mamarios no neoplĆ”sicos mediante Illumina Human Methylation 450K BeadChip. Estos datos se analizaron desde dos enfoques bioinformĆ”ticos diferentes. Concluimos que el patrĆ³n epigenĆ©tico (metiloma de DNA y acetiloma de histonas) estĆ” alterado en CMTN respecto a tejido mamario no neoplĆ”sico. AsĆ­ como que la hipometilaciĆ³n de ADAM12 y la acetilaciĆ³n de H4K5 son potenciales biomarcadores de peor pronĆ³stico y que ADAM12 es una potencial diana terapĆ©utica en CMTN. TambiĆ©n sugerimos la utilidad diagnĆ³stica de una nueva firma basada en metilaciĆ³n de DNA y las diferencias entre los genes regulados por la acetilaciĆ³n de H4K6ac segĆŗn la naturaleza de las lĆ­neas (no neoplĆ”sicas o TNBC).
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    PublicationOpen Access
    A DNA methylation-based gene signature can predict triple-negative breast cancer diagnosis
    (MDPI, 2021) Mendaza Lainez, Saioa; Guerrero Setas, David; Monreal Santesteban, IƱaki; Ulazia Garmendia, Ane; CĆ³rdoba Iturriagagoitia, Alicia; Cruz, Susana de la; MartĆ­n SĆ”nchez, Esperanza; Ciencias de la Salud; Osasun Zientziak; Universidad PĆŗblica de Navarra / Nafarroako Unibertsitate Publikoa
    Triple-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.
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    PublicationOpen Access
    Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix
    (MDPI, 2020) Mendaza Lainez, Saioa; FernĆ”ndez Irigoyen, JoaquĆ­n; SantamarĆ­a MartĆ­nez, Enrique; Zudaire, Tamara; Guarch, Rosa; Guerrero Setas, David; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua; Universidad PĆŗblica de Navarra / Nafarroako Unibertsitate Publikoa
    The 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 ā€“SCCCs). CC cell proliferation and invasion were monitored by real-time cell analysis and TranswellĀ® 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.
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    PublicationOpen 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, IƱaki; CĆ³rdoba Iturriagagoitia, Alicia; Ruiz de AzĆŗa, Yerani; Ciencias de la Salud; Osasun Zientziak; Universidad PĆŗblica de Navarra / Nafarroako Unibertsitate Publikoa
    Triple-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.