4.6 Article

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

Journal

CELLS
Volume 12, Issue 11, Pages -

Publisher

MDPI
DOI: 10.3390/cells12111462

Keywords

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

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The expression of ABC transporter ABCA7 is aberrantly regulated in breast cancer. Epigenetic and genetic alterations, as well as alternative splicing variants, were investigated in ABCA7 in breast cancer. CpG methylation abnormalities were observed at the exon 5-intron 5 boundary in a subtype-specific manner. Treatment with chemotherapeutic agents altered ABCA7 intron levels and dysregulated splicing factors.
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.

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