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Mitochondria Autoimmunity and MNRR1 in Breast Carcinogenesis: A Review.

ABSTRACT: We review here the evidence for participation of mitochondrial autoimmunity in BC inception and progression and propose a new paradigm that may challenge the prevailing thinking in oncogenesis by suggesting that mitochondrial autoimmunity is a major contributor to breast carcinogenesis and probably to the inception and progression of other solid tumors. It has been shown that MNRR1 mediated mitochondrial-nuclear function promotes BC cell growth and migration and the development of metastasis and constitutes a proof of concept supporting the participation of mitochondrial autoimmunity in breast carcinogenesis. The resemblance of the autoantibody profile in BC detected by IFA with that in the rheumatic autoimmune diseases suggested that studies on the autoantibody response to tumor associated antigens and the characterization of the mtDNA- and nDNA-encoded antigens may provide functional data on breast carcinogenesis. We also review the studies supporting the view that a panel of autoreactive nDNA-encoded mitochondrial antigens in addition to MNRR1 may be involved in breast carcinogenesis. These include GAPDH, PKM2, GSTP1, SPATA5, MFF, ncRNA PINK1-AS/DDOST as probably contributing to BC progression and metastases and the evidence suggesting that DDX21 orchestrates a complex signaling network with participation of JUND and ATF3 driving chronic inflammation and breast tumorigenesis. We suggest that the widespread autoreactivity of mtDNA- and nDNA-encoded mitochondrial proteins found in BC sera may be the reflection of autoimmunity triggered by mitochondrial and non-mitochondrial tumor associated antigens involved in multiple tumorigenic pathways. Furthermore, we suggest that mitochondrial proteins may contribute to mitochondrial dysfunction in BC even if mitochondrial respiration is found to be within normal limits. However, although the studies show that mitochondrial autoimmunity is a major factor in breast cancer inception and progression, it is not the only factor since there is a multiplex autoantibody profile targeting centrosome and stem cell antigens as well as anti-idiotypic antibodies, revealing the complex signaling network involved in breast carcinogenesis. In summary, the studies reviewed here open new, unexpected therapeutic avenues for cancer prevention and treatment of patients with cancer derived from an entirely new perspective of breast carcinogenesis.

SUBMITTER: Madrid FF

PROVIDER: S-EPMC7894625 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mitochondria Autoimmunity and MNRR1 in Breast Carcinogenesis: A Review.

Madrid Félix Fernández FF Grossman Lawrence I LI Aras Siddhesh S

Journal of cancer immunology 20201201 4

We review here the evidence for participation of mitochondrial autoimmunity in BC inception and progression and propose a new paradigm that may challenge the prevailing thinking in oncogenesis by suggesting that mitochondrial autoimmunity is a major contributor to breast carcinogenesis and probably to the inception and progression of other solid tumors. It has been shown that MNRR1 mediated mitochondrial-nuclear function promotes BC cell growth and migration and the development of metastasis and ...[more]

PMID: 33615312

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Project description:BACKGROUND:Autoantibodies function as markers of tumorigenesis and have been proposed to enhance early detection of malignancies. We recently reported, using immunoscreening of a T7 complementary DNA (cDNA) library of breast cancer (BC) proteins with sera from patients with BC, the presence of autoantibodies targeting several mitochondrial DNA (mtDNA)-encoded subunits of the electron transport chain (ETC) in complexes I, IV, and V. METHODS:In this study, we have characterized the role of Mitochondrial-Nuclear Retrograde Regulator 1 (MNRR1, also known as CHCHD2), identified on immunoscreening, in breast carcinogenesis. We assessed the protein as well as transcript levels of MNRR1 in BC tissues and in derived cell lines representing tumors of graded aggressiveness. Mitochondrial function was also assayed and correlated with the levels of MNRR1. We studied the invasiveness of BC derived cells and the effect of MNRR1 levels on expression of genes associated with cell proliferation and migration such as Rictor and PGC-1?. Finally, we manipulated levels of MNRR1 to assess its effect on mitochondria and on some properties linked to a metastatic phenotype. RESULTS:We identified a nuclear DNA (nDNA)-encoded mitochondrial protein, MNRR1, that was significantly associated with the diagnosis of invasive ductal carcinoma (IDC) of the breast by autoantigen microarray analysis. In focusing on the mechanism of action of MNRR1 we found that its level was nearly twice as high in malignant versus benign breast tissue and up to 18 times as high in BC cell lines compared to MCF10A control cells, suggesting a relationship to aggressive potential. Furthermore, MNRR1 affected levels of multiple genes previously associated with cancer metastasis. CONCLUSIONS:MNRR1 regulates multiple genes that function in cell migration and cancer metastasis and is higher in cell lines derived from aggressive tumors. Since MNRR1 was identified as an autoantigen in breast carcinogenesis, the present data support our proposal that both mitochondrial autoimmunity and MNRR1 activity in particular are involved in breast carcinogenesis. Virtually all other nuclear encoded genes identified on immunoscreening of invasive BC harbor an MNRR1 binding site in their promoters, thereby placing MNRR1 upstream and potentially making it a novel marker for BC metastasis.

Dataset Information

Mitochondria Autoimmunity and MNRR1 in Breast Carcinogenesis: A Review.

Publications

Mitochondria Autoimmunity and MNRR1 in Breast Carcinogenesis: A Review.

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