Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer

Deya Obaidat; Roberta Giordo; Erica L Kleinbrink; Emilia Banisad; Lawrence I Grossman; Rooshan Arshad; Azadeh Stark; Marie-Claire Maroun; Leonard Lipovich; Félix Fernandez-Madrid

doi:10.3389/fgene.2022.970619

Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer

Front Genet. 2023 Mar 29:13:970619. doi: 10.3389/fgene.2022.970619. eCollection 2022.

Authors

Affiliations

¹ Department of Internal Medicine, Division of Rheumatology, Wayne State University School of Medicine, Detroit, MI, United States.
² Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.
³ Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States.
⁴ Quantitative Life Sciences, McGill University, Montreal, QC, Canada.
⁵ Department of Pathology, Henry Ford Health System, Detroit, MI, United States.
⁶ Shenzhen Huayuan Biotechnology Co. Ltd, Shenzhen Huayuan Biological Science Research Institute, Shenzhen, Guangdong, China.
⁷ Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.

Abstract

Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients' sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3' untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment.

Keywords: autoimmunity; breast cancer; carcinogenesis; long non-coding RNA; mitochondria; phage display.

Grants and funding

This research was funded in part by NIH R01 CA 122277 to FF (PI), “Development and validation of a panel of breast cancer autoantigens for the early diagnosis of breast cancer,” and in part by the Flora Temple Fund, from Mrs. Mary Webber Parker through the Detroit Medical Center, by the NIH Director’s New Innovator Award 1DP2-CA196375 to LL (PI); by the Mohammed Bin Rashid University Internal Research Grant to LL and the Mohammed Bin Rashid University Postdoctoral Fellowship to RG and by the Al Jalila Foundation.