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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2020

01-12-2020 | Breast Cancer | Primary research

Clinicopathological and prognostic significance of nestin expression in patients with breast cancer: a systematic review and meta-analysis

Authors: Xinyi Zhang, Changsheng Xing, Wenting Guan, Lang Chen, Kai Guo, Anze Yu, Kai Xie

Published in: Cancer Cell International | Issue 1/2020

Login to get access

Abstract

Background

Nestin has been revealed to promote tumorigenesis, progression, metastasis, and angiogenesis of breast cancer. Although the prognostic and clinicopathological impact of nestin expression on breast cancer patients has been assessed in several independent studies, their results remained conflicting. Therefore, we performed this meta-analysis to elucidate the prognostic and clinicopathological association of nestin expression with breast cancer.

Methods

A comprehensive literature search was performed in the electronic databases PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), and the Wangfang Data. The statistical analysis was conducted using Stata 15.0 and Review Manager 5.3.

Results

A total of 15 studies with 6066 breast cancer patients were included in this meta-analysis. Pooled results indicated that positive expression of nestin was significantly associated with reduced breast cancer-specific survival (BCSS, univariate analysis, HR = 2.11, 95% CI [1.79, 2.49], P < 0.00001; multivariate analysis, HR = 1.30, 95% CI [1.06, 1.60], P = 0.01), worse overall survival (OS, univariate analysis, HR = 1.88, 95% CI [1.31, 2.71], P = 0.0007; multivariate analysis, HR = 1.89, 95% CI [1.34, 2.67], P = 0.0003) and poorer recurrence-free survival (univariate analysis, HR = 2.60, 95% CI [1.52, 4.46], P = 0.0005), but not with distant metastasis-free survival in univariate analysis (P > 0.05). In addition, increased nestin expression was correlated with younger age, higher tumor grade, larger tumor size, positive blood vessel invasion and high vascular proliferation index, but not with lymph node metastasis or lymph vessel invasion. Nestin was preferentially expressed in invasive ductal carcinoma, triple-negative breast cancer and basal-like subtypes. Nestin expression was inversely associated with the expression of ER and PR, but not with HER-2. Conversely, nestin expression was positively correlated with the expression of basal-like markers CK5, P-cadherin and EGFR. Moreover, nestin expression was strongly associated with the presence of five basal-like profiles (BLP1-5).

Conclusions

This meta-analysis revealed the prognostic value and clinicopathological significance of nestin expression in breast cancer. Nestin is an independent prognostic factor for worse BCSS and OS of breast cancer patients. Nestin is also a valuable biomarker for unfavorable clinicopathological features and tumor angiogenesis of breast cancer. Therefore, nestin is a promising therapeutic target for malignant breast cancer, especially for TNBC and basal-like phenotype.
Appendix
Available only for authorised users
Literature
1.
DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438–51.PubMedCrossRef
2.
Zardavas D, Irrthum A, Swanton C, Piccart M. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol. 2015;12(7):381–94.PubMedCrossRef
3.
Fu NY, Nolan E, Lindeman GJ, Visvader JE. Stem cells and the differentiation hierarchy in mammary gland development. Physiol Rev. 2020;100(2):489–523.PubMedCrossRef
4.
Fang Y, Zhang Q, Wang X, Yang X, Wang X, Huang Z, Jiao Y, Wang J. Quantitative phosphoproteomics reveals genistein as a modulator of cell cycle and DNA damage response pathways in triple-negative breast cancer cells. Int J Oncol. 2016;48(3):1016–28.PubMedPubMedCentralCrossRef
5.
van Reesema LLS, Zheleva V, Winston JS, Jansen RJ, O’Connor CF, Isbell AJ, Bian M, Qin R, Bassett PT, Hinson VJ, et al. SIAH and EGFR, two RAS pathway biomarkers, are highly prognostic in locally advanced and metastatic breast cancer. EBioMedicine. 2016;11:183–98.PubMedPubMedCentralCrossRef
6.
7.
Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.CrossRefPubMed
8.
van ‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530–6.PubMedCrossRef
9.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869–74.PubMedCrossRefPubMedCentral
10.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100(14):8418–23.PubMedCrossRefPubMedCentral
11.
Matsen CB, Neumayer LA. Breast cancer: a review for the general surgeon. JAMA Surg. 2013;148(10):971–9.PubMedCrossRef
12.
Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel M. Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the primary therapy of early breast cancer 2015. Ann Oncol. 2015;26(8):1533–46.PubMedPubMedCentralCrossRef
13.
Aebi S, Gelber S, Anderson SJ, Lang I, Robidoux A, Martin M, Nortier JW, Paterson AH, Rimawi MF, Canada JM, et al. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol. 2014;15(2):156–63.PubMedPubMedCentralCrossRef
14.
Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, Dobbs HJ, Hopwood P, Lawton PA, Magee BJ, et al. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet Oncol. 2013;14(11):1086–94.PubMedCrossRef
15.
Fan W, Chang J, Fu P. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Fut Med Chem. 2015;7(12):1511–9.CrossRef
16.
Smith A, Farrah K. In: Gene expression profiling tests for breast cancer: a rapid qualitative review. Ottawa (ON); 2019.
17.
Jia Y, Chen Y, Wang Q, Jayasinghe U, Luo X, Wei Q, Wang J, Xiong H, Chen C, Xu B, et al. Exosome: emerging biomarker in breast cancer. Oncotarget. 2017;8(25):41717–33.PubMedPubMedCentralCrossRef
18.
Jafari SH, Saadatpour Z, Salmaninejad A, Momeni F, Mokhtari M, Nahand JS, Rahmati M, Mirzaei H, Kianmehr M. Breast cancer diagnosis: imaging techniques and biochemical markers. J Cell Physiol. 2018;233(7):5200–13.PubMedCrossRef
19.
Duffy MJ, Walsh S, McDermott EW, Crown J. Biomarkers in breast cancer: where are we and where are we going? Adv Clin Chem. 2015;71:1–23.PubMedCrossRef
20.
Zhao ZW, Lu P, Zhang H, Xu HM, Gao NN, Li M, Liu CG. Nestin positively regulates the Wnt/beta-catenin pathway and the proliferation, survival and invasiveness of breast cancer stem cells. Breast Cancer Res. 2014;16(4):408.PubMedPubMedCentralCrossRef
21.
Asleh K, Won JR, Gao DX, Voduc KD, Nielsen TO. Nestin expression in breast cancer: association with prognosis and subtype on 3641 cases with long-term follow-up. Breast Cancer Res Treat. 2018;168(1):107–15.PubMedCrossRef
22.
De Lara S, Nyqvist J, Werner Rönnerman E, Helou K, Kenne Sarenmalm E, Einbeigi Z, Karlsson P, Parris TZ, Kovács A. The prognostic relevance of FOXA1 and Nestin expression in breast cancer metastases: a retrospective study of 164 cases during a 10-year period (2004–2014). BMC Cancer. 2019;19(1):187.PubMedPubMedCentralCrossRef
23.
Gao NN, Xu H, Liu CG, Xu HM, Chen GL, Wang XM, Li YY, Wang Y. Nestin: predicting specific survival factors for breast cancer. Tumor Biol. 2014;35(3):1751–5.CrossRef
24.
Kruger K, Wik E, Knutsvik G, Nalwoga H, Klingen TA, Arnes JB, Chen Y, Mannelqvist M, Dimitrakopoulou K, Stefansson IM, et al. Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer. Sci Rep. 2017;7(1):1089.PubMedPubMedCentralCrossRef
25.
Liu C, Cao X, Zhang Y, Xu H, Zhang R, Wu Y, Lu P, Jin F. Co-expression of Oct-4 and Nestin in human breast cancers. Mol Biol Rep. 2012;39(5):5875–81.PubMedCrossRef
26.
Liu CG, Chen B, Zhu J, Zhang RS, Yao F, Jin F, Xu HM, Lu P. Clinical implications for nestin protein expression in breast cancer. Cancer Sci. 2010;101(3):815–9.PubMedCrossRef
27.
Parry S, Savage K, Marchiò C, Reis-Filho JS. Nestin is expressed in basal-like and triple negative breast cancers. J Clin Pathol. 2008;61(9):1045–50.PubMedCrossRef
28.
Piras F, Ionta MT, Lai S, Perra MT, Atzori F, Minerba L, Pusceddu V, Maxia C, Murtas D, Demurtas P, et al. Nestin expression associates with poor prognosis and triple negative phenotype in locally advanced (T4) breast cancer. Eur J Histochem. 2011;55(4):e39.PubMedPubMedCentralCrossRef
29.
30.
31.
Cheng F, Eriksson JE. Intermediate filaments and the regulation of cell motility during regeneration and wound healing. Cold Spring Harb Perspect Biol. 2017;9(9):a022046.PubMedPubMedCentralCrossRef
32.
Li H, Cherukuri P, Li N, Cowling V, Spinella M, Cole M, Godwin AK, Wells W, DiRenzo J. Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res. 2007;67(2):501–10.PubMedCrossRef
33.
34.
Costa CD, Justo AA, Kobayashi PE, Story MM, Palmieri C, Laufer Amorim R, Fonseca-Alves CE. Characterization of OCT3/4, Nestin, NANOG, CD44 and CD24 as stem cell markers in canine prostate cancer. Int J Biochem Cell Biol. 2019;108:21–8.PubMedCrossRef
35.
Jin X, Jin X, Jung JE, Beck S, Kim H. Cell surface Nestin is a biomarker for glioma stem cells. Biochem Biophys Res Commun. 2013;433(4):496–501.PubMedCrossRef
36.
Kleeberger W, Bova GS, Nielsen ME, Herawi M, Chuang AY, Epstein JI, Berman DM. Roles for the stem cell associated intermediate filament Nestin in prostate cancer migration and metastasis. Cancer Res. 2007;67(19):9199–206.PubMedPubMedCentralCrossRef
37.
38.
Vlashi E, Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin Cancer Biol. 2015;31:28–35.PubMedCrossRef
39.
40.
Ladstein RG, Bachmann IM, Straume O, Akslen LA. Nestin expression is associated with aggressive cutaneous melanoma of the nodular type. Mod Pathol. 2014;27(3):396–401.PubMedCrossRef
41.
Tsujimura T, Makiishi-Shimobayashi C, Lundkvist J, Lendahl U, Nakasho K, Sugihara A, Iwasaki T, Mano M, Yamada N, Yamashita K, et al. Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal. Am J Pathol. 2001;158(3):817–23.PubMedPubMedCentralCrossRef
42.
Wang J, Cai J, Huang Y, Ke Q, Wu B, Wang S, Han X, Wang T, Wang Y, Li W, et al. Nestin regulates proliferation and invasion of gastrointestinal stromal tumor cells by altering mitochondrial dynamics. Oncogene. 2016;35(24):3139–50.PubMedCrossRef
43.
Yamahatsu K, Matsuda Y, Ishiwata T, Uchida E, Naito Z. Nestin as a novel therapeutic target for pancreatic cancer via tumor angiogenesis. Int J Oncol. 2012;40(5):1345–57.PubMed
44.
Cros J, Sbidian E, Posseme K, Letierce A, Guettier C, Benoit G, Ferlicot S. Nestin expression on tumour vessels and tumour-infiltrating macrophages define a poor prognosis subgroup of pt1 clear cell renal cell carcinoma. Virchows Arch. 2016;469(3):331–7.PubMedCrossRef
45.
Takakuwa O, Maeno K, Kunii E, Ozasa H, Hijikata H, Uemura T, Kasai D, Ohkubo H, Miyazaki M, Oguri T, et al. Involvement of intermediate filament nestin in cell growth of small-cell lung cancer. Lung Cancer. 2013;81(2):174–9.PubMedCrossRef
46.
Zhao L, Li J, Liu M, Zhou H, Zou H, Wei Y, Sun K, Li G, Li S, Pang L. The clinicopathological parameters significance of CD133 and Nestin in epithelial ovarian cancer: a meta-analysis. Future Oncol. 2017;13(28):2555–70.PubMedCrossRef
47.
Li S, Lai Y, Fan J, Shen C, Che G. Clinicopathological and prognostic significance of Nestin expression in patients with non-small cell lung cancer: a systematic review and meta-analysis. Clin Exp Med. 2017;17(2):161–74.PubMedCrossRef
48.
Lv D, Lu L, Hu Z, Fei Z, Liu M, Wei L, Xu J. Nestin expression is associated with poor clinicopathological features and prognosis in glioma patients: an association study and meta-analysis. Mol Neurobiol. 2017;54(1):727–35.PubMedCrossRef
49.
Wu B, Sun C, Feng F, Ge M, Xia L. Do relevant markers of cancer stem cells CD133 and Nestin indicate a poor prognosis in glioma patients? A systematic review and meta-analysis. J Exp Clin Cancer Res. 2015;34:44.PubMedPubMedCentralCrossRef
50.
Nowak A, Grzegrzolka J, Paprocka M, Piotrowska A, Rys J, Matkowski R, Dziegiel P. Nestin-positive microvessel density is an independent prognostic factor in breast cancer. Int J Oncol. 2017;51(2):668–76.PubMedCrossRef
51.
Nowak A, Grzegrzółka J, Kmiecik A, Piotrowska A, Matkowski R, Dziȩgiel P. Role of nestin expression in angiogenesis and breast cancer progression. Int J Oncol. 2018;52(2):527–35.PubMed
52.
Asleh K, Lyck Carstensen S, Tykjaer Jorgensen CL, Burugu S, Gao D, Won JR, Jensen MB, Balslev E, Laenkholm AV, Nielsen DL, et al. Basal biomarkers nestin and INPP4B predict gemcitabine benefit in metastatic breast cancer: samples from the phase III SBG0102 clinical trial. Int J Cancer. 2019;144(10):2578–86.PubMedCrossRef
53.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.PubMedPubMedCentralCrossRef
54.
Meisen WH, Dubin S, Sizemore ST, Mathsyaraja H, Thies K, Lehman NL, Boyer P, Jaime-Ramirez AC, Elder JB, Powell K, et al. Changes in BAI1 and nestin expression are prognostic indicators for survival and metastases in breast cancer and provide opportunities for dual targeted therapies. Mol Cancer Ther. 2015;14(1):307–14.PubMedCrossRef
55.
Tampaki EC, Tampakis A, Nonni A, Kontzoglou K, Patsouris E, Kouraklis G. Nestin and cluster of differentiation 146 expression in breast cancer: predicting early recurrence by targeting metastasis? Tumour Biol. 2017;39(3):1010428317691181.PubMedCrossRef
56.
Zhu J, Liu CG, Zhang RS, Lu Y, Jin F, Xu HM, Lu P. Relationship between nestin expression and other clinicopathological factors in breast cancer. J Chin Clin Med. 2009;4(11):622–5.
57.
Marmor S, Hui JYC, Huang JL, Kizy S, Beckwith H, Blaes AH, Rueth NM, Tuttle TM. Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast. Cancer. 2017;123(16):3015–21.PubMedCrossRef
58.
Suzuki S, Namiki J, Shibata S, Mastuzaki Y, Okano H. The neural stem/progenitor cell marker nestin is expressed in proliferative endothelial cells, but not in mature vasculature. J Histochem Cytochem. 2010;58(8):721–30.PubMedPubMedCentralCrossRef
59.
Kruger K, Stefansson IM, Collett K, Arnes JB, Aas T, Akslen LA. Microvessel proliferation by co-expression of endothelial nestin and Ki-67 is associated with a basal-like phenotype and aggressive features in breast cancer. Breast. 2013;22(3):282–8.PubMedCrossRef
60.
Ye X, Brabletz T, Kang Y, Longmore GD, Nieto MA, Stanger BZ, Yang J, Weinberg RA. Upholding a role for EMT in breast cancer metastasis. Nature. 2017;547(7661):E1–3.PubMedPubMedCentralCrossRef
61.
Onisim A, Achimas-Cadariu A, Vlad C, Kubelac P, Achimas-Cadariu P. Current insights into the association of Nestin with tumor angiogenesis. J BUON. 2015;20(3):699–706.PubMed
62.
Wang Y, Li C, Li Y, Zhu Z. Involvement of breast cancer stem cells in tumor angiogenesis. Oncol Lett. 2017;14(6):8150–5.PubMedPubMedCentral
63.
Nowak A, Dziegiel P. Implications of nestin in breast cancer pathogenesis (Review). Int J Oncol. 2018;53(2):477–87.PubMed
64.
Bussolati B, Grange C, Sapino A, Camussi G. Endothelial cell differentiation of human breast tumour stem/progenitor cells. J Cell Mol Med. 2009;13(2):309–19.PubMedCrossRef
65.
Mokry J, Cizkova D, Filip S, Ehrmann J, Osterreicher J, Kolar Z, English D. Nestin expression by newly formed human blood vessels. Stem Cells Dev. 2004;13(6):658–64.PubMedCrossRef
66.
Liang ZW, Wang Z, Chen H, Li C, Zhou T, Yang Z, Yang X, Yang Y, Gao G, Cai W. Nestin-mediated cytoskeletal remodeling in endothelial cells: novel mechanistic insight into VEGF-induced cell migration in angiogenesis. Am J Physiol Cell Physiol. 2015;308(5):C349–58.PubMedCrossRef
67.
Asleh-Aburaya K, Sheffield BS, Kos Z, Won JR, Wang XQ, Gao D, Wolber R, Gilks CB, Bernard PS, Chia SK, et al. Basal biomarkers nestin and INPP4b identify intrinsic subtypes accurately in breast cancers that are weakly positive for oestrogen receptor. Histopathology. 2017;70(2):185–94.PubMedCrossRef
68.
Rogelsperger O, Ekmekcioglu C, Jager W, Klimpfinger M, Konigsberg R, Krenbek D, Sellner F, Thalhammer T. Coexpression of the melatonin receptor 1 and nestin in human breast cancer specimens. J Pineal Res. 2009;46(4):422–32.PubMedCrossRef
69.
Yuan L, Collins AR, Dai J, Dubocovich ML, Hill SM. MT(1) melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells. Mol Cell Endocrinol. 2002;192(1–2):147–56.PubMedCrossRef
70.
Kiefer T, Ram PT, Yuan L, Hill SM. Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells. Breast Cancer Res Treat. 2002;71(1):37–45.PubMedCrossRef
71.
Dillon DC, Easley SE, Asch BB, Cheney RT, Brydon L, Jockers R, Winston JS, Brooks JS, Hurd T, Asch HL. Differential expression of high-affinity melatonin receptors (MT1) in normal and malignant human breast tissue. Am J Clin Pathol. 2002;118(3):451–8.PubMedCrossRef
72.
Jockers R, Maurice P, Boutin JA, Delagrange P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what’s new? Br J Pharmacol. 2008;154(6):1182–95.PubMedPubMedCentralCrossRef
Metadata
Title
Clinicopathological and prognostic significance of nestin expression in patients with breast cancer: a systematic review and meta-analysis
Authors
Xinyi Zhang
Changsheng Xing
Wenting Guan
Lang Chen
Kai Guo
Anze Yu
Kai Xie
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01252-5

Other articles of this Issue 1/2020

Cancer Cell International 1/2020 Go to the issue

Primary research

Silencing of miR-17-5p suppresses cell proliferation and promotes cell apoptosis by directly targeting PIK3R1 in laryngeal squamous cell carcinoma

Review

Reshaping the role of m6A modification in cancer transcriptome: a review

Primary research

Immune-related long non-coding RNA signature identified prognosis and immunotherapeutic efficiency in bladder cancer (BLCA)

Review

The clinical prognostic value of lncRNA FAM83H-AS1 in cancer patients: a meta-analysis

Correction

Correction to: Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression

Primary research

Prognostic value of a five-lncRNA signature in esophageal squamous cell carcinoma
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