title: MCM2: An alternative to Ki-67 for measuring breast cancer cell proliferation.
abstract: Breast cancer is a heterogeneous disease comprising a diversity of tumor subtypes that manifest themselves in a wide variety of clinical, pathological, and molecular features. One important subset, luminal breast cancers, comprises two clinically distinct subtypes luminal A and B each of them endowed with its own genetic program of differentiation and proliferation. Luminal breast cancers were operationally defined as follows: Luminal A: ER+, PR+, HER2-, Ki-67<14% and Luminal B: ER+ and/or PR+, HER2-,Ki-67≥14% or, alternatively ER+ and/or PR+, HER2+, any Ki-67. There is currently a need for a clinically robust and validated immunohistochemical assay that can help distinguish between luminal A and B breast cancer. MCM2 is a family member of the minichromosome maintenance protein complex whose role in DNA replication and cell proliferation is firmly established. As MCM2 appears to be an attractive alternative to Ki-67, we sought to study the expression of MCM2 and Ki-67 in different histological grades and molecular subtypes of breast cancer focusing primarily on ER-positive tumors. MCM2 and Ki-67 mRNA expression were studied using in silico analysis of available DNA microarray and RNA-sequencing data of human breast cancer. We next used immunohistochemistry to evaluate protein expression of MCM2 and Ki-67 on tissue microarrays of invasive breast carcinoma. We found that MCM2 and Ki-67 are highly expressed in breast tumors of high histological grades, comprising clinically aggressive tumors such as triple-negative, HER2-positive and luminal B subtypes. MCM2 expression was detected at higher levels than that of Ki-67 in normal breast tissues and in breast cancers. The bimodal distribution of MCM2 scores in ER+/HER2- breast tumors led to the identification of two distinct subgroups with different relapse-free survival rates. In conclusion, MCM2 expression can help sorting out two clinically important subsets of luminal breast cancer whose treatment and clinical outcomes are likely to diverge.
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada.|Department of Histology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
authors.forename: Einas M
authors.initials: EM
authors.lastname: Yousef
authors.affiliation: Cancer Research Centre at Laval University, Quebec City, QC, Canada.|Oncology Axis, CHU of Quebec Research Center, Hôpital du Saint-Sacrement, Quebec City, QC, Canada.|Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Furrer
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada.
authors.forename: David L
authors.initials: DL
authors.lastname: Laperriere
authors.affiliation: The University of Montreal Hospital Research Centre, Montreal, QC, Canada.
authors.forename: Muhammad R
authors.initials: MR
authors.lastname: Tahir
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada.|Department of Biochemistry, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mader
authors.affiliation: Cancer Research Centre at Laval University, Quebec City, QC, Canada.|Oncology Axis, CHU of Quebec Research Center, Hôpital du Saint-Sacrement, Quebec City, QC, Canada.|Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada.|Deschênes-Fabia Center for Breast Diseases, Hôpital du St-Sacrement, Quebec City, QC, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Diorio
authors.affiliation: Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada.|Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
authors.forename: Louis A
authors.initials: LA
authors.lastname: Gaboury
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000145:classification* / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis / Q000096:biosynthesis; D064111:Minichromosome Maintenance Complex Component 2 / Q000032:analysis / Q000096:biosynthesis*; D060787:Neoplasm Grading / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2