Article Data

  • Views 984
  • Dowloads 179

Original Research

Open Access

The expression and prognostic value of minichromosome maintenance markers in human breast cancer: a comprehensive analysis

  • Jieqiong Xie1
  • Yulin Zhou1,*,
  • Yunsheng Ge1,*,

1United Diagnostic and Research Center for Clinical Genetics, Women and Children’s Hospital, School of Medicine & School of Public Health, Xiamen University, 361104 Xiamen, Fujian, China

DOI: 10.31083/j.ejgo4302029 Vol.43,Issue 2,April 2022 pp.227-237

Submitted: 09 October 2021 Accepted: 27 December 2021

Published: 15 April 2022

*Corresponding Author(s): Yulin Zhou E-mail: zhou_yulin@126.com
*Corresponding Author(s): Yunsheng Ge E-mail: gshee@163.com

Abstract

Objective: Breast cancer (BC) is one of the most health-threatening neoplasms for women worldwide. Despite advances in detection and treatment strategies over the past few decades, the current biomarkers of BC are less than satisfactory for effective prognosis and individualized treatment. This study aimed to investigate the new biomarkers to meet this urgent demand. Methods: The current study investigated the transcriptional levels of minichromosome maintenance genes (MCMs) in BC patients from the Oncomine, UALCAN database, and Gene Expression Profiling Interactive Analysis (GEPIA); protein expression levels of MCM proteins in BC patients were derived from the Human Protein Atlas (HPA) database. Further, survival analysis was evaluated with Kaplan-Meier Plotter. BC genome atlas data were obtained from cBioPortal databases. Gene regulatory network analysis was performed using the STRING online tool, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using DAVID. Results: Based on multiple database analysis, mRNA and protein levels of MCM2, MCM4 and MCM10 were much higher in BC patient, and survival analysis showed that high transcription levels of most MCMs were found to be associated with poor prognosis for BC patients; moreover, the MCMs genetic alterations, especially of MCM2, MCM4 and MCM10, were found in 45% of BC patients. In addition, dysregulation of MCMs was considered to possibly affect DNA damage/repair, cell cycle dysregulation and chromosome instability. Conclusions: In summary, this study indicated that MCM2, MCM4, and MCM10 are potential prognostic markers and therapeutic targets for BC.


Keywords

Minichromosome maintenance gene family; Breast cancer; mRNA expression level; Prognostic marker; Bioinformatics

analysis

Cite and Share

Jieqiong Xie,Yulin Zhou,Yunsheng Ge. The expression and prognostic value of minichromosome maintenance markers in human breast cancer: a comprehensive analysis. European Journal of Gynaecological Oncology. 2022. 43(2);227-237.

References

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018; 68: 394–424.

[2] Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncology. 2017; 3: 524–548.

[3] Fan S, Yang Z, Ke Z, Huang K, Liu N, Fang X, et al. Down-regulation of the long non-coding RNA TUG1 is associated with cell proliferation, migration, and invasion in breast cancer. Biomedicine & Pharmacotherapy. 2017; 95: 1636–1643.

[4] Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2011; 23: vii11–vii19.

[5] Troisi R, Bjørge T, Gissler M, Grotmol T, Kitahara CM, Myrtveit Sæther SM, et al. The role of pregnancy, perinatal factors and hormones in maternal cancer risk: a review of the evidence. Journal of Internal Medicine. 2018; 283: 430–445.

[6] Harbeck N, Gnant M. Breast cancer. The Lancet. 2017; 389: 1134–1150.

[7] Zimmermann M, de Lange T. 53BP1: pro choice in DNA repair. Trends in Cell Biology. 2014; 24: 108–117.

[8] Li N, Zhai Y, Zhang Y, Li W, Yang M, Lei J, et al. Structure of the eukaryotic MCM complex at 3.8 Å. Nature. 2015; 524: 186–191.

[9] Jenkinson ER, Chong JPJ. Minichromosome maintenance helicase activity is controlled by N-and C-terminal motifs and requires the ATPase domain helix-2 insert. Proceedings of the National Academy of Sciences. 2006; 103: 7613–7618.

[10] Kang S, Warner M, Bell S. Multiple Functions for Mcm2–7 AT-Pase Motifs during Replication Initiation. Molecular Cell. 2014; 55: 655–665.

[11] Samel SA, Fernández-Cid A, Sun J, Riera A, Tognetti S, Herrera MC, et al. A unique DNA entry gate serves for regulated loading of the eukaryotic replicative helicase MCM2–7 onto DNA. Genes & Development. 2014; 28: 1653–1666.

[12] Fragkos M, Ganier O, Coulombe P, Méchali M. DNA replication origin activation in space and time. Nature Reviews Molecular Cell Biology. 2015; 16: 360–374.

[13] Yu Z, Feng D, Liang C. Pairwise Interactions of the Six Human MCM Protein Subunits. Journal of Molecular Biology. 2004; 340: 1197–1206.

[14] Kearsey SE, Labib K. MCM proteins: evolution, properties, and role in DNA replication. Biochimica Et Biophysica Acta (BBA)-Gene Structure and Expression. 1998; 1398: 113–136.

[15] Tye BK. MCM Proteins in DNA Replication. Annual Review of Biochemistry. 1999; 68: 649–686.

[16] Kreuter A, Jesse M, Potthoff A, Brockmeyer NH, Gambichler T, Stücker M, et al. Expression of proliferative biomarkers in anal intraepithelial neoplasia of HIV-positive men. Journal of the American Academy of Dermatology. 2010; 63: 490–498.

[17] Schimmack S, Lawrence B, Kenney B, Schmitz-Winnenthal H, Modlin IM, Kidd M. Minichromosome Maintenance Expression Defines Slow-Growing Gastroenteropancreatic Neuroendocrine Neoplasms. Translational Oncology. 2016; 9: 411–418.

[18] Kikuchi J, Kinoshita I, Shimizu Y, Kikuchi E, Takeda K, Aburatani H, et al. Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer. Lung Cancer. 2011; 72: 229–237.

[19] Kwok HF, Zhang SD, McCrudden CM, Yuen HF, Ting KP, Wen Q, et al. Prognostic significance of minichromosome maintenance proteins in breast cancer. American Journal of Cancer Research. 2015; 5: 52–71.

[20] Hua C, Zhao G, Li Y, Bie L. Minichromosome Maintenance (MCM) Family as potential diagnostic and prognostic tumor markers for human gliomas. BMC Cancer. 2014; 14: 526.

[21] Liu Z, Li J, Chen J, Shan Q, Dai H, Xie H, et al. MCM family in HCC: MCM6 indicates adverse tumor features and poor out-comes and promotes S/G2 cell cycle progression. BMC Cancer. 2018; 18: 200.

[22] Wang M, Xie S, Yuan W, Xie T, Jamal M, Huang J, Yin Q, Song H, Zhang Q. Minichromosome maintenance protein 10 as a marker for proliferation and prognosis in lung cancer. International Journal of Oncology. 2019; 55: 1349–1360.

[23] Peng YP, Zhu Y, Yin LD, Zhang JJ, Guo S, Fu Y, Miao Y, Wei JS. The Expression and Prognostic Roles of MCMs in Pancreatic Cancer. PLoS ONE. 2016; 11: e0164150.

[24] Wojnar A, Kobierzycki C, Krolicka A, Pula B, Podhorska-Okolow M, Dziegiel P. Correlation of Ki-67 and MCM-2 prolif-erative marker expression with grade of histological malignancy (G) in ductal breast cancers. Folia Histochemica et Cytobiolog-ica. 2010; 48: 442–446.

[25] Yang WD, Wang L. MCM10 facilitates the invaded/migrated potentials of breast cancer cells via Wnt/β-catenin signaling and is positively interlinked with poor prognosis in breast carcinoma. Journal of Biochemical and Molecular Toxicology. 2019; 33: e22330.

[26] Thul PJ, Lindskog C. The human protein atlas: a spatial map of the human proteome. Protein Science. 2018; 27: 233–244.

[27] Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000; 406: 747–752.

[28] Curtis C, Shah SP, Chin S, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012; 486: 346–352.

[29] Glück S, Ross JS, Royce M, McKenna EF, Perou CM, Avisar E, et al. TP53 genomics predict higher clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine ± trastuzumab. Breast Cancer Research and Treatment. 2012; 132: 781–791.

[30] Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006; 9: 121–132.

[31] Zhao H, Langerød A, Ji Y, Nowels KW, Nesland JM, Tibshirani R, et al. Different Gene Expression Patterns in Invasive Lobular and Ductal Carcinomas of the Breast. Molecular Biology of the Cell. 2004; 15: 2523–2536.

[32] Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal. Science Signaling. 2013; 6: pl1.

[33] Simon NE, Schwacha A. The Mcm2-7 Replicative Helicase: a Promising Chemotherapeutic Target. BioMed Research International. 2014; 2014: 1–14.

[34] Tachibana KK, Gonzalez MA, Coleman N. Cell-cycle-dependent regulation of DNA replication and its relevance to cancer pathology. The Journal of Pathology. 2005; 205: 123–129.

[35] Liu Y, Wang B, Jiang Y, Cao J, Hao J, Zhang Y, et al. MCMs expression in lung cancer: implication of prognostic significance. Journal of Cancer. 2017; 8: 3641–3647.

[36] Hennessy KM, Lee A, Chen E, Botstein D. A group of interacting yeast DNA replication genes. Genes & Development. 1991; 5: 958–969.

[37] Gibson SI, Surosky RT, Tye BK. The phenotype of the minichro-mosome maintenance mutant mcm3 is characteristic of mutants defective in DNA replication. Molecular and Cellular Biology. 1990; 10: 5707–5720.

[38] Pramila T, Miles S, GuhaThakurta D, Jemiolo D, Breeden LL. Conserved homeodomain proteins interact with MADS box protein Mcm1 to restrict ECB-dependent transcription to the M/G1 phase of the cell cycle. Genes & Development. 2002; 16: 3034–3045.

[39] Labib K. How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? Genes & Development. 2010; 24: 1208–1219.

[40] Gakiopoulou H, Korkolopoulou P, Levidou G, Thymara I, Saetta A, Piperi C, et al. Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications. British Journal of Cancer. 2007; 97: 1124–1134.

[41] Yang C, Wen Y, Li H, Zhang D, Zhang N, Shi X, et al. Overex-pression of minichromosome maintenance 2 predicts poor prognosis in patients with gastric cancer. Oncology Reports. 2012; 27: 135–142.

[42] Obermann EC, Went P, Zimpfer A, Tzankov A, Wild PJ, Stoehr R, et al. Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in diffuse large B-cell lymphoma: a tissue microarray and clinicopathological analy-sis. BMC Cancer. 2005; 5: 162.

[43] Deng M, Sun J, Xie S, Zhen H, Wang Y, Zhong A, et ak. Inhibition of MCM2 enhances the sensitivity of ovarian cancer cell to carboplatin. Molecular Medicine Reports. 2019; 20: 2258–2266.

[44] Gonzalez MA, Pinder SE, Callagy G, Vowler SL, Morris LS, Bird K, et al. Minichromosome Maintenance Protein 2 is a Strong Independent Prognostic Marker in Breast Cancer. Journal of Clinical Oncology. 2003; 21: 4306–4313.

[45] Shima N, Buske TR, Schimenti JC. Genetic Screen for Chromo-some Instability in Mice: Mcm4 and Breast Cancer. Cell Cycle. 2007; 6: 1135–1140.

[46] Shima N, Alcaraz A, Liachko I, Buske TR, Andrews CA, Munroe RJ, et al. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nature Genetics. 2007; 39: 93–98.

[47] Quan Y, Xia Y, Liu L, Cui J, Li Z, Cao Q, et al. Cell-Cycle-Regulated Interaction between Mcm10 and Double Hexameric Mcm2-7 is Required for Helicase Splitting and Activation during S Phase. Cell Reports. 2015; 13: 2576–2586.

[48] Homesley L, Lei M, Kawasaki Y, Sawyer S, Christensen T, Tye BK. Mcm10 and the MCM2–7 complex interact to initiate DNA synthesis and to release replication factors from origins. Genes & Development. 2000; 14: 913–926.

[49] Zhao Y, Wang Y, Zhu F, Zhang J, Ma X, Zhang D. Gene expression profiling revealed MCM3 to be a better marker than Ki67 in prognosis of invasive ductal breast carcinoma patients. Clinical and Experimental Medicine. 2020; 20: 249–259.

[50] Braidotti P, Nuciforo P, Mollenhauer J, Poustka A, Pellegrini C, Moro A, et al. DMBT1 expression is down-regulated in breast cancer. BMC Cancer. 2004; 4: 46.

[51] Huang T, Huo L, Wang Y, Xia W, Wei Y, Chang S, et al. Epidermal Growth Factor Receptor Potentiates MCM7-Mediated DNA Replication through Tyrosine Phosphorylation of Lyn Kinase in Human Cancers. Cancer Cell. 2013; 23: 796–810.

[52] AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U, et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. Journal of Clinical Investigation. 2015; 125: 258–262.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,500 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Biological Abstracts Easily discover critical journal coverage of the life sciences with Biological Abstracts, produced by the Web of Science Group, with topics ranging from botany to microbiology to pharmacology. Including BIOSIS indexing and MeSH terms, specialized indexing in Biological Abstracts helps you to discover more accurate, context-sensitive results.

Google Scholar Google Scholar is a freely accessible web search engine that indexes the full text or metadata of scholarly literature across an array of publishing formats and disciplines.

JournalSeek Genamics JournalSeek is the largest completely categorized database of freely available journal information available on the internet. The database presently contains 39226 titles. Journal information includes the description (aims and scope), journal abbreviation, journal homepage link, subject category and ISSN.

Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.

BIOSIS Previews BIOSIS Previews is an English-language, bibliographic database service, with abstracts and citation indexing. It is part of Clarivate Analytics Web of Science suite. BIOSIS Previews indexes data from 1926 to the present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Submission Turnaround Time

Conferences

Top