Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis.
Autoantigens
/ metabolism
Autoimmunity
Breast Neoplasms
/ diagnosis
Carcinoma, Ductal, Breast
/ diagnosis
Cell Line, Tumor
Cell Movement
Cell Proliferation
DNA-Binding Proteins
Female
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Mitochondria
/ genetics
Mitochondrial Proteins
/ genetics
Neoplasm Invasiveness
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ genetics
Prospective Studies
Protein Array Analysis
Rapamycin-Insensitive Companion of mTOR Protein
/ genetics
Transcription Factors
/ genetics
Up-Regulation
Autoantibodies
Breast cancer
Metastasis
Mitochondria
Nuclear encoded mitochondrial gene
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
02 May 2019
02 May 2019
Historique:
received:
03
01
2019
accepted:
03
04
2019
entrez:
4
5
2019
pubmed:
3
5
2019
medline:
20
8
2019
Statut:
epublish
Résumé
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. 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-1α. Finally, we manipulated levels of MNRR1 to assess its effect on mitochondria and on some properties linked to a metastatic phenotype. 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. 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.
Sections du résumé
BACKGROUND
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
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-1α. Finally, we manipulated levels of MNRR1 to assess its effect on mitochondria and on some properties linked to a metastatic phenotype.
RESULTS
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
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.
Identifiants
pubmed: 31046734
doi: 10.1186/s12885-019-5575-7
pii: 10.1186/s12885-019-5575-7
pmc: PMC6498478
doi:
Substances chimiques
Autoantigens
0
CHCHD2 protein, human
0
DNA-Binding Proteins
0
Mitochondrial Proteins
0
PPARGC1A protein, human
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
RICTOR protein, human
0
Rapamycin-Insensitive Companion of mTOR Protein
0
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Pagination
411Subventions
Organisme : NCI NIH HHS
ID : R01 CA122277
Pays : United States
Organisme : National Institutes of Health
ID : R01 CA122277
Organisme : U.S. Department of Defense
ID : W81XWH-16-1-0516
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