Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Metastasis | Research article

Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis

Authors: Siddhesh Aras, Marie-Claire Maroun, Yeohan Song, Sudeshna Bandyopadhyay, Azadeh Stark, Zeng-Quan Yang, Michael P. Long, Lawrence I. Grossman, Félix Fernández-Madrid

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

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-1α. 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.
Literature
1.
Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol Biomark Prev. 2017;26(6):809–15.CrossRef
2.
Miller JW, Hanson V, Johnson GD, Royalty JE, Richardson LC. From cancer screening to treatment: service delivery and referral in the national breast and cervical cancer early detection program. Cancer. 2014;120(Suppl 16):2549–56.CrossRefPubMed
3.
Desantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 2017;67(6):439–48.CrossRefPubMed
4.
5.
Fernandez-Madrid F, Maroun MC, Olivero OA, Long M, Stark A, Grossman LI, et al. Autoantibodies in breast cancer sera are not epiphenomena and may participate in carcinogenesis. BMC Cancer. 2015;15:407.CrossRefPubMedCentral
6.
Maroun MC, Grossman LI, Lancaster WD, Long M, Arshad R, Aboukasm G, et al. Mitochondrial encoded targets of breast cancer anti-mitochondrial antibodies implications of mitochondrial autoimmunity for breast cancer progression. Sci J Molec Biomarkers Diag. 2017;1(1):001–8.
7.
Aras S, Arrabi H, Purandare N, Hüttemann M, Kamholz J, Zuchner S, et al. Abl2 kinase phosphorylates bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. Biochim Biophys Acta. 2017;1864(2):440–8.CrossRef
8.
Aras S, Bai M, Lee I, Springett R, Hüttemann M, Grossman LI. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015;20:43–51.CrossRefPubMed
9.
Aras S, Pak O, Sommer N, Finley R Jr, Hüttemann M, Weissmann N, et al. Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2. Nucleic Acids Res. 2013;41(4):2255–66.CrossRefPubMedPubMedCentral
10.
Hüttemann M, Lee I, Liu J, Grossman LI. Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element. FEBS J. 2007;274(21):5737–48.CrossRefPubMed
11.
Wei Y, Vellanki RN, Coyaud E, Ignatchenko V, Li L, Krieger JR, et al. CHCHD2 is coamplified with EGFR in NSCLC and regulates mitochondrial function and cell migration. Mol Cancer Res. 2015;13(7):1119–29.CrossRefPubMed
12.
Song R, Yang B, Gao X, Zhang J, Sun L, Wang P, et al. Cyclic adenosine monophosphate response element-binding protein transcriptionally regulates CHCHD2 associated with the molecular pathogenesis of hepatocellular carcinoma. Mol Med Rep. 2015;11(6):4053–62.CrossRefPubMedPubMedCentral
13.
Fernandez-Madrid F, Tang N, Alansari H, Granda JL, Tait L, Amirikia KC, et al. Autoantibodies to annexin xi-a and other autoantigens in the diagnosis of breast cancer. Cancer Res. 2004;64(15):5089–96.CrossRefPubMed
14.
Wolman SR, Heppner GH. Genetic heterogeneity in breast cancer. J Natl Cancer Inst. 1992;84(7):469–70.CrossRefPubMed
15.
Purandare N, Somayajulu M, Hüttemann M, Grossman LI, Aras S. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): partners in mitochondrial and nuclear function and dysfunction. J Biol Chem. 2018;293(17):6517–29.CrossRefPubMedPubMedCentral
16.
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215(3):403–10.CrossRefPubMed
17.
18.
Benaki D, Zikos C, Evangelou A, Livaniou E, Vlassi M, Mikros E, et al. Solution structure of humanin, a peptide against Alzheimer's disease-related neurotoxicity. Biochem Biophys Res Commun. 2005;329(1):152–60.CrossRefPubMed
19.
Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J, et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One. 2009;4(7):e6146.CrossRefPubMedPubMedCentral
20.
Soule HD, Maloney TM, Wolman SR, Peterson WD Jr, Brenz R, Mcgrath CM, et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res. 1990;50(18):6075–86.PubMed
21.
Chung S, Yao J, Suyama K, Bajaj S, Qian X, Loudig OD, et al. N-cadherin regulates mammary tumor cell migration through AKT3 suppression. Oncogene. 2013;32(4):422–30.CrossRefPubMed
22.
Grottke A, Ewald F, Lange T, Norz D, Herzberger C, Bach J, et al. Downregulation of AKT3 increases migration and metastasis in triple negative breast cancer cells by upregulating s100a4. PLoS One. 2016;11(1):e0146370.CrossRefPubMedPubMedCentral
23.
Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, et al. AKT/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. FASEB J. 2001;15(11):1953–62.CrossRefPubMed
24.
Morrison Joly M, Hicks DJ, Jones B, Sanchez V, Estrada MV, Young C, et al. RICTOR/MTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res. 2016;76(16):4752–64.CrossRefPubMed
25.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of AKT/PKB by the rictor-mtor complex. Science. 2005;307(5712):1098–101.CrossRefPubMed
26.
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92(6):829–39.CrossRefPubMed
27.
Lebleu VS, O'connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16(10):992–1003 1001–1015.CrossRefPubMedPubMedCentral
28.
Porporato PE, Payen VL, Perez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 2014;8(3):754–66.CrossRefPubMed
29.
Sotgia F, Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, et al. Mitochondrial metabolism in cancer metastasis: visualizing tumor cell mitochondria and the “reverse Warburg effect” in positive lymph node tissue. Cell Cycle. 2012;11(7):1445–54.CrossRefPubMedPubMedCentral
30.
Kong H, Chandel NS. Regulation of redox balance in cancer and T cells. J Biol Chem. 2018;293(20):7499–507.CrossRefPubMed
31.
Seo M, Lee WH, Suk K. Identification of novel cell migration-promoting genes by a functional genetic screen. FASEB J. 2010;24(2):464–78.CrossRefPubMed
32.
Liu Y, Clegg HV, Leslie PL, Di J, Tollini LA, He Y, et al. CHCHD2 inhibits apoptosis by interacting with BCL-xL to regulate BAX activation. Cell Death Differ. 2015;22(6):1035–46.CrossRefPubMed
33.
Lai X, Umbricht CB, Fisher K, Bishop J, Shi Q, Chen S. Identification of novel biomarker and therapeutic target candidates for diagnosis and treatment of follicular carcinoma. J Proteome. 2017;166:59–67.CrossRef
34.
Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP, Sotgia F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 2014;5(22):11029–37.CrossRefPubMedPubMedCentral
35.
Liberman L, Menell JH. Breast imaging reporting and data system (bi-rads). Radiol Clin N Am. 2002;40(3):409–30 v.CrossRefPubMed
36.
Eberl MM, Fox CH, Edge SB, Carter CA, Mahoney MC. Bi-rads classification for management of abnormal mammograms. J Am Board Fam Med. 2006;19(2):161–4.CrossRefPubMed
37.
38.
Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;357(9255):539–45.CrossRefPubMed
39.
40.
41.
42.
Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–64.CrossRefPubMed
43.
Tschopp O, Yang ZZ, Brodbeck D, Dummler BA, Hemmings-Mieszczak M, Watanabe T, et al. Essential role of protein kinase b gamma (PKB gamma/AKT3) in postnatal brain development but not in glucose homeostasis. Development. 2005;132(13):2943–54.CrossRefPubMed
44.
Linnerth-Petrik NM, Santry LA, Petrik JJ, Wootton SK. Opposing functions of AKT isoforms in lung tumor initiation and progression. PLoS One. 2014;9(4):e94595.CrossRefPubMedPubMedCentral
Metadata
Title
Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis
Authors
Siddhesh Aras
Marie-Claire Maroun
Yeohan Song
Sudeshna Bandyopadhyay
Azadeh Stark
Zeng-Quan Yang
Michael P. Long
Lawrence I. Grossman
Félix Fernández-Madrid
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5575-7

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

Dipeptidyl-peptidase-4 (DPP-4) inhibitor ameliorates 5-flurouracil induced intestinal mucositis

Research article

Circulating microRNAs miR-331 and miR-195 differentiate local luminal a from metastatic breast cancer

Research article

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations

Research article

Clinical factors associated with treatment outcomes in EGFR mutant non-small cell lung cancer patients with brain metastases: a case-control observational study

Research article

Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial

Research article

Apparent diffusion coefficient cannot predict molecular subtype and lymph node metastases in invasive breast cancer: a multicenter analysis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits