Cited by 653Gene expression and cancer classificationBreast Cancer Treatment StudiesCancer-related Molecular Pathways

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Common markers of proliferation

Whitfield, Michael L., George, Lacy K., Grant, Gavin D., Perou, Charles M.·2006·Nature Reviews Cancer

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Abstract

When normal tissue and tumour samples are compared by microarray analysis, the biggest differences most often occur in the expression levels of genes that control cell proliferation. However, this difference is detected whenever mRNA samples that are taken from two cell populations with different proliferation rates are compared. Although the exact genes that comprise this 'proliferation signature' often differ, they are almost always genes that are involved in the fundamental process of cell proliferation. Can the proliferation signature be used to improve our understanding of the cell cycle and cancer pathogenesis, as well as being used as a biomarker for cancer diagnosis and prognosis?

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Genetically Targeted Fractionated Chemotherapy
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“Overexpression of genes has also been documented in malignant cells, which can also be used to serve as biomarkers [16].”
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Angiogenesis in Adipose Tissue: How can Moderate Caloric Restriction Affects Obesity-Related Endothelial Dysfunction?
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Stabilization of GTSE1 by cyclin D1–CDK4/6-mediated phosphorylation promotes cell proliferation with implications for cancer prognosisPreprint
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A 3D Bioprinted Pancreatic Cancer Model Using Collagen-Gelatin Methacrylamide-Alginate Bioinks to Mimic the Desmoplastic Microenvironment
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“51,52 We observed a significantly higher expression of Ki67 in the GAC2 model compared to those of GAC0, GAC1, and Col1.”
MiR-31 suppresses lung adenocarcinoma cell proliferation through CDK1 and E2F2-mediated cell cycle arrest
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Inhibiting cyclin D1–CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline
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“However, cell cycle and proliferation-promoting genes 25 were not upregulated by CCND1 or CDK6 knockdown or palbociclib treatment (Extended Data Fig.”
A genetic variant in the immune-related gene ERAP1 affects colorectal cancer prognosis
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Breast milk induces the differentiation of monocytes into macrophages, promoting human cytomegalovirus infection
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“We used several additional assays to confirm the cell proliferation results, including the Click-iT Plus EdU Cell Proliferation imaging assay as well as an immunofluorescence staining assay that targets the cell proliferation marker, Ki67 (52, 53).”
Identification of a rank-based radiomic signature with individualized prognostic value for lung adenocarcinoma in a multi-cohort study
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Proximity Proteomics Reveals USP44 Forms a Complex with BRCA2 in Neuroblastoma Cells and Is Required to Prevent Chromosome Breakage
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Heteronemin suppresses EGF‑induced proliferation through the PI3K/PD‑L1 signaling pathways in cholangiocarcinoma
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Research progress on cancer-related epigenetic switches
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“%) showed the shortest median OS and MFS. Patients with dual-low expression (SMYD3-low/ASCL2-low) demonstrated optimal prognosis, while those exhibiting discordant expression patterns (SMYD3-low/ASCL2-high or SMYD3-high/ASCL2-low) displayed intermediate clinical outcomes [14].”
Influential
Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations
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“We speci ﬁ cally considered key markers that are either upregulated during epithelial-mesenchymal transition (EMT) — an indirect proxy for tumor migration and invasion phenotypes — or other gene markers commonly shared by cell proliferation programs 41,42 .”
Finding Influential Genes Using Gene Expression Data and Boolean Models of Metabolic Networks
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“Many of them are classified into two categories: sequence-based approach [12] and expressionbased approach [31].”
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Jha, N. K., Jha, S. K., Sharma, A., Yadav, R., Pandey, P., Kesari, K. K., Kumar, N., Nand, P., Agrahari, M., & Gupta, N. S. (2020) · Springer eBooks · doi:10.1007/978-981-15-1991-8_9 · Cited by 3
Stemness Correlates Inversely with MHC Class I Expression in Pediatric Small Round Blue Cell Tumors
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“Non classical MHC class I proteins (HLA‐E/‐F/‐G) were also negatively correlated with the mRNAsi, while proliferation genes such as BUB1B, CCNB1, and MKI67 were positively correlated with the mRNAsi (similar findings were observed for other previously reported prolifer‐ ation genes [25]: BUB1, CCNB1, CCNE1, MYBL2, PLK…”
BackgroundResult
Differential expression of genes influencing mitotic processes in cord blood mononuclear cells after a pre-conceptional micronutrient-based randomised controlled trial: Pune Rural Intervention in Young Adolescents (PRIYA)
Khare, S., Madhok, A., Patta, I., Sukla, K. K., Wagh, V. V., Kunte, P. S., RAUT, D. A., Bhat, D., Kumaran, K., Fall, C. H. D., et al. (2023) · Journal of Developmental Origins of Health and Disease · doi:10.1017/s204017442200068x · Cited by 3
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“One of these proteins is CyclinD1, which is encoded by the CCND1 gene (35, 36).”
Background
Computational identification of DNA damage-relevant lncRNAs for predicting therapeutic efficacy and clinical outcomes in cancer
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“39,40 This progressive development of supporting cells is also seen between DIV16 and DIV21, with further repression of Sox11 and Top2a and upregulation of supporting cell genes Otoa , Otol1 , and Tecta (Figure 5E).”
A case of intraparotid schwannoma in a juvenile: Clinical, pathological, ultrastructural, and immunohistopathological study, including an examination of Ki-67 and MCM-3 expressions
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“Although the pathological examination of major salivary gland tumors should be based on an evaluation of histopathological features, evaluation of proliferation markers and ultrastructure of the tumor may help in understanding the pathology of the assessed neoplasms [5,6].”
Background
Extraction of peroxisome proliferator-activated receptor α agonist-induced lipid metabolism-related and unrelated genes in rat liver and analysis of their genomic location
Mizukawa, Y., Amagase, Y., & Urushidani, T. (2020) · The Journal of Toxicological Sciences · doi:10.2131/jts.45.449 · Cited by 3
“Of these, dose- and time-dependency of the induction of three genes, geminin (Gmnn, 1378056_at), topoisomerase IIα (Topo2a, 1372186_a_at), and marker of proliferation Ki-67 (Mki67, 1374775_at), which are established gene markers of proliferation (Whitfield et al., 2006), are shown in Fig.”
Metabolism-Related Gene Pairs to Predict the Clinical Outcome and Molecular Characteristics of Early Hepatocellular Carcinoma
Wu, J., Lin, Z., Ji, D., Li, Z., Zhang, H., Lu, S., Wang, S., Liu, X., & Ao, L. (2022) · Cancers · doi:10.3390/cancers14163957 · Cited by 3
“The average expression levels of 43 proliferation-associated genes were also used to calculate the proliferation scores [29] (Supplementary Table S3).”
BackgroundMethod
Chromosome instability leaves its mark
Pollack, J. R. (2006) · Nature Genetics · doi:10.1038/ng0906-973 · Cited by 3
Spatial Heterogeneity of Infiltrating T cells in High-Grade Serous Ovarian Cancer revealed by Multi-omics analysisPreprint
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Zheng, J., Xie, Z., Niu, L., Zheng, G., Li, R., Dan, H., Duan, L., Wu, H., Ren, G., Dou, X., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1984416/v1 · Cited by 5
Saturated fatty acid-inducible miR-103-3p impairs the myogenic differentiation of progenitor cells by enhancing cell proliferation through Twinfilin-1/F-actin/YAP1 axis
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“Additionally, we further analyzed the expression levels of CCNB1, CCND1, and PCNA, which are known to induce cell proliferation and cell cycle progression [32], using qRT-PCR to confirm the effect of miR-103-3p on cell proliferation.”
Method
From resistance to Response: Metallic nanoparticles as game changers in triple negative breast cancer therapy
Vikal, A., Maurya, R., Patel, P., Narang, R. K., & Kurmi, B. D. (2025) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2025.107322 · Cited by 3
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“This rejuvenated group included genes related to cell cycle progression ( top2 , cdk4 , cdk7 , and eif4 ) (Whitfield et al. 2006) and ER stress response ( atf4 , hsp90b1 , pfdn2 , and ddit3 ), which were downregulated with age but upregulated in aged (Tm) samples (Figure 3B and Figure S8C).”
miR-138-5p overexpression inhibits limbal epithelial cell proliferation and induces cell cycle arrest, in vitro
Suiwal, S., Stachon, T., Kumar, V., Fries, F. N., Hsu, S.-L., Liu, S., Li, S., Kundu, S., Seitz, B., Amini, M., et al. (2026) · Experimental Eye Research · doi:10.1016/j.exer.2026.110934 · Cited by 2
Identification of mutational signature for lung adenocarcinoma prognosis and immunotherapy prediction
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“Molecular scores including proliferation [20], stemness [21] and hypoxia [22] scores of samples were investigated based on their mRNA expression profiles (see Supplementary Methods).”
Background
FLII Modulates the Myogenic Differentiation of Progenitor Cells via Actin Remodeling-Mediated YAP1 Regulation
Nguyen, M. T., Ly, Q. K., Kim, H., & Lee, W. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814335 · Cited by 2
“In addition, we determined the transcript levels of PCNA, CCNB1, and CCND1, which are known to induce cell cycle progression and proliferation [26], to verify the effect of siFLII on cell proliferation.”
Background
WAVE2 Is a Vital Regulator in Myogenic Differentiation of Progenitor Cells through the Mechanosensitive MRTFA–SRF Axis
Nguyen, M. T., Ly, Q. K., Kim, H., & Lee, W. (2023) · Cells · doi:10.3390/cells13010009 · Cited by 2
“In addition, we analyzed the transcript levels of proliferating cell nuclear antigen (PCNA), cyclin B1, and cyclin D1, which promote the cell cycle and proliferation [44].”
Method
Vδ1 T Cells Integrated in Full-Thickness Skin Equivalents: A Model for the Role of Human Skin–Resident γδT Cells
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Porras‐Gómez, T. J., & Moreno-Méndoza, N. (2024) · Zygote · doi:10.1017/s0967199424000364 · Cited by 2
Enhanced Natural Killer Cell Proliferation by Stress‐Induced Feeder Cells
Lee, D., Song, M., & Kwon, S. (2025) · Biotechnology and Bioengineering · doi:10.1002/bit.28951 · Cited by 2
“The selected markers included MKI67 , which indicates ongoing cell cycle progression (Koskinen Holm and Qu 2022; Whitfield et al. 2006); PCNA involved in forming a protein complex crucial for DNA replication during the DNA synthesis phase (Kubben et al. 1994; Whitfield et al. 2006); and MCM2 ,…”
Influential
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Kiran, S., Xue, Y., Sarker, D. B., & Sang, Q. A. (2025) · Cancers · doi:10.3390/cancers17060997 · Cited by 2
“Caspase-9 is involved in caspase-dependent apoptosis [47], whereas Ki-67 is a marker of tumor cell proliferation [48,49].”
Viral‐Directed Augmentation of Kupffer Cell Cross‐Presentation Provokes Antitumor Immunity Against Liver Metastasis
Chen, C., Zhang, Q., Li, J., Zhou, X., Gao, D., Li, L., Huang, D.-B., Wang, J.-Z., & Zeng, Z.-T. (2025) · Advancement of science · doi:10.1002/advs.202504929 · Cited by 5
Trophic and temporal dynamics of macrophage biology in human inner ear organogenesis
Deng, Y., Ehiogu, B., Luca, E., Dabdoub, A., Cao, K. L., Wells, C. A., & Nayagam, B. A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1690583 · Cited by 2
“Speci ﬁ cally, Mac 7 populations were enriched for genes implicated in important roles in cell proliferation ( MELK ) (20), cell division ( BUB1 and KIF11 ) (21), DNA synthesis and repair ( POLQ and RRM2 ) (22), and cytoskeletal remodeling ( DIAPH3 ) (23, 24).”
Biomarkers for Breast Cancer: Towards the Proposition of Clinically Relevant Tools
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Chondrocyte Turnover in Lung Cartilage
Gopar‐Cuevas, Y., Niderhauser‐García, A., Ancer-Arellano, A., Miranda-Maldonado, I. C., Chávez-Briones, M.-D.-L., Rodríguez‐Flores, L. E., Ortega‐Martínez, M., & Jaramillo‐Rangel, G. (2018) · InTech eBooks · doi:10.5772/intechopen.70860 · Cited by 2
Identification and Characterization of Genes Related to the Prognosis of Hepatocellular Carcinoma Based on Single-Cell Sequencing
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“This may explain why HCC patients gradually develop drug resistance after targeted therapy for a certain period [8, 19].”

Authors: Whitfield, M. L., George, L. K., Grant, G. D., & Perou, C. M.
Affiliations: Dartmouth College (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Whitfield, Michael L.
ORCID: Whitfield, Michael L.
Grant, Gavin D.
Perou, Charles M.
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2006-02
Volume: 6
Issue: 2
Pages: 99-106
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc1802
OpenAlex: W2018173663
Cited by: 650
References: 66
Citations by year: 2026: 31 · 2025: 46 · 2024: 35 · 2023: 54 · 2022: 53 · 2021: 54 · 2020: 33 · 2019: 29 · 2018: 22 · 2017: 27 · 2016: 34 · 2015: 15 · 2014: 17 · 2013: 27 · 2012: 26
FWCI: 2.57
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: cell proliferation, proliferation signature, gene expression profiling, tumor markers, cell cycle, carcinogenesis, cancer diagnosis, cancer prognosis
MeSH terms: Cell Cycle, Genetic Markers, Humans, Neoplasms, Prognosis, RNA, Messenger, Biomarkers, Tumor, Gene Expression Profiling, Cell Proliferation

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