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

Saioa Mendaza1, Ane Ulazia-Garmendia1, Iñaki Monreal-Santesteban1

  • 1Molecular 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.

International Journal of Molecular Sciences
|February 6, 2020
PubMed

Insights

Triple-negative breast cancer (TNBC) shows exclusive hypomethylation in three genes, including ADAM12. ADAM12 hypomethylation predicts worse outcomes and suggests it as a therapeutic target for TNBC.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
  • Epigenetic alterations, particularly DNA methylation, are prevalent in TNBC.
  • Identifying novel biomarkers and therapeutic targets is crucial for TNBC management.

Purpose of the Study:

  • To identify potential DNA methylation biomarkers and therapeutic targets in TNBC.
  • To investigate the role of specific hypomethylated genes in TNBC progression and treatment response.
  • To evaluate ADAM12 as both a prognostic biomarker and a therapeutic target.

Main Methods:

  • Genome-wide DNA methylation analysis using Illumina Human Methylation 450K BeadChip on TNBC and non-neoplastic tissues.
  • Validation of methylation status by pyrosequencing in an independent cohort.
  • Assessment of protein expression via immunohistochemistry.
  • Functional analysis of ADAM12 using gene silencing (shRNA) in TNBC cell lines.

Main Results:

  • Three genes (VWCE, TSPAN9, ADAM12) were exclusively hypomethylated in TNBC.
  • ADAM12 hypomethylation correlated with worse prognosis in TNBC and was detected in adjacent tissues and plasma.
  • ADAM12 silencing reduced TNBC cell proliferation and migration and enhanced doxorubicin sensitivity.

Conclusions:

  • ADAM12 hypomethylation serves as a potential poor outcome biomarker in TNBC.
  • ADAM12 represents a promising therapeutic target for triple-negative breast cancer.
  • Epigenetic profiling can uncover actionable targets in aggressive cancer subtypes.
Keywords:
ADAM12DNA methylationepigenetic biomarkerstherapeutic targettriple-negative breast cancer

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