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Open AccessArticle

ADAM12 is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer

1
Molecular Pathology of Cancer Group, Navarrabiomed, ComplejoHospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain
2
Department of Pathology, ComplejoHospitalario de Navarra (CHN), Irunlarrea 3, 31008, Pamplona, Spain
3
Department of Surgery, ComplejoHospitalario de Navarra, (CHN), Irunlarrea 3, 31008, Pamplona, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(3), 903; https://doi.org/10.3390/ijms21030903
Received: 14 January 2020 / Revised: 28 January 2020 / Accepted: 28 January 2020 / Published: 30 January 2020
(This article belongs to the Section Molecular Oncology)
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. View Full-Text
Keywords: ADAM12; DNA methylation; triple-negative breast cancer; epigenetic biomarkers; therapeutic target ADAM12; DNA methylation; triple-negative breast cancer; epigenetic biomarkers; therapeutic target
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Mendaza, S.; Ulazia-Garmendia, A.; Monreal-Santesteban, I.; Córdoba, A.; Azúa, Y.R.; Aguiar, B.; Beloqui, R.; Armendáriz, P.; Arriola, M.; Martín-Sánchez, E.; Guerrero-Setas, D. ADAM12 is A Potential Therapeutic Target Regulated by Hypomethylation in Triple-Negative Breast Cancer. Int. J. Mol. Sci. 2020, 21, 903.

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