Aberrant DNA Methylation, Expression, and Occurrence of Transcript Variants of the ABC Transporter ABCA7 in Breast Cancer

Katja Zappe, Antonio Kopic, Alexandra Scheichel, Ann Katrin Schier, Lukas Emanuel Schmidt, Yasmin Borutzki, Heidi Miedl, Martin Schreiber, Theresa Mendrina, Christine Pirker, Georg Pfeiler, Stefan Hacker, Werner Haslik, Dietmar Pils, Andrea Bileck, Christopher Gerner, Samuel Meier-Menches, Petra Heffeter, Margit Cichna-Markl (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

The ABC transporter ABCA7 has been found to be aberrantly expressed in a variety of cancer types, including breast cancer. We searched for specific epigenetic and genetic alterations and alternative splicing variants of ABCA7 in breast cancer and investigated whether these alterations are associated with ABCA7 expression. By analyzing tumor tissues from breast cancer patients, we found CpGs at the exon 5–intron 5 boundary aberrantly methylated in a molecular subtype-specific manner. The detection of altered DNA methylation in tumor-adjacent tissues suggests epigenetic field cancerization. In breast cancer cell lines, DNA methylation levels of CpGs in promoter-exon 1, intron 1, and at the exon 5–intron 5 boundary were not correlated with ABCA7 mRNA levels. By qPCR involving intron-specific and intron-flanking primers, we identified intron-containing ABCA7 mRNA transcripts. The occurrence of intron-containing transcripts was neither molecular subtype-specific nor directly correlated with DNA methylation at the respective exon–intron boundaries. Treatment of breast cancer cell lines MCF-7, BT-474, SK-BR3, and MDA-MB-231 with doxorubicin or paclitaxel for 72 h resulted in altered ABCA7 intron levels. Shotgun proteomics revealed that an increase in intron-containing transcripts was associated with significant dysregulation of splicing factors linked to alternative splicing.

Original languageEnglish
Article number1462
JournalCells
Volume12
Issue number11
DOIs
Publication statusPublished - Jun 2023

Austrian Fields of Science 2012

  • 106002 Biochemistry
  • 301114 Cell biology
  • 301904 Cancer research

Keywords

  • ABC transporter
  • ABCA7
  • alternative splicing
  • breast cancer
  • DNA methylation
  • doxorubicin
  • gene expression
  • intron retention/altered intron termination
  • mass spectrometry-based shotgun proteomics
  • paclitaxel

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