Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Meta-Analysis

LGR5 As a Potential Therapeutic Target for Breast Cancer: A Systematic Review and Meta-analysis

Author(s): Seyedeh-Kiana Razavi-Amoli, Versa Omrani-Nava, Keyvan Heydari, Dilyara Kaidarova and Reza Alizadeh-Navaei*

Volume 18, Issue 5, 2023

Published on: 21 November, 2022

Page: [690 - 698] Pages: 9

DOI: 10.2174/1574888X18666221014144642

Price: $65

conference banner
Abstract

Background and Objective: Breast cancer is the world's most common malignancy. Despite significant advances in the diagnosis and treatment of the disease, the associated mortality rate is still high. Tumor initiating cells known as cancer stem cells with unique abilities are suspected responsible for therapy failure and poor prognosis. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a cancer stem cell marker that promotes aggressive features in breast cancer cells. So, the aim of this study was to perform a systematic review and meta-analysis to evaluate LGR5 as a therapeutic target for breast cancer.

Methods: This systematic review and meta-analysis were performed using databases of Web of Science, Scopus, and PubMed. We searched these databases with LGR5 and Breast Cancer and related keywords based on the mesh database until Oct12, 2021. All studies that reported the rate of LGR5 high expression with Immunohistochemistry in breast cancer patients were included in this review. We used the STATA and random effect models for data analysis.

Results: Finally, 7 studies including 2632 breast cancer samples were studied. The pooled prevalence of LGR5 high expression in breast cancer was 48.6 % (CI95%: 40.5-56.7%, I2=0.0) and in triple negative was 48.6% (CI95%: 38.4-58.7%, I2= 0.0).

Conclusion: Our findings show that the rate of LGR5 high expression in breast cancer in general and especially in triple-negative was considerable and it seems that this is a potential therapeutic target for breast cancer.

Keywords: LGR5, therapeutic target, breast cancer, cancer stem cell, triple negative, immunohistochemistry, gene expression.

Graphical Abstract
[1]
Warrier S, Patil M, Bhansali S, Varier L, Sethi G. Designing precision medicine panels for drug refractory cancers targeting cancer stemness traits. Biochim Biophys Acta Rev Cancer 2021; 1875(1): 188475.
[http://dx.doi.org/10.1016/j.bbcan.2020.188475] [PMID: 33188876]
[2]
Katz SJ, Jagsi R, Morrow M. Reducing overtreatment of cancer with precision medicine. JAMA 2018; 319(11): 1091-2.
[http://dx.doi.org/10.1001/jama.2018.0018] [PMID: 29470568]
[3]
Saeg F, Anbalagan M. Breast cancer stem cells and the challenges of eradication: A review of novel therapies. Stem Cell Investig 2018; 5: 39.
[http://dx.doi.org/10.21037/sci.2018.10.05] [PMID: 30498750]
[4]
Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH. Overview of Cancer Stem Cells (CSCs) and mechanisms of their regulation: Implications for cancer therapy.In: Curr Protoc Pharmacol. United States: Wiley 2013.
[5]
Zhang M, Li Z, Zhang X, Chang Y. Cancer stem cells as a potential therapeutic target in breast cancer. Stem Cell Investig 2014; 1(7): 14.
[PMID: 27358860]
[6]
Meehan J, Gray M, Martínez PC, et al. Precision medicine and the role of biomarkers of radiotherapy response in breast cancer. Front Oncol 2020; 10(628): 628.
[http://dx.doi.org/10.3389/fonc.2020.00628] [PMID: 32391281]
[7]
Walcher L, Kistenmacher AK,, Suo H, et al. Cancer stem cells—origins and biomarkers: Perspectives for targeted personalized therapies. Front Immunol 2020; 11(1280): 1280.
[http://dx.doi.org/10.3389/fimmu.2020.01280] [PMID: 32849491]
[8]
Plaks V, Kong N, Werb Z. The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015; 16(3): 225-38.
[http://dx.doi.org/10.1016/j.stem.2015.02.015] [PMID: 25748930]
[9]
Morgan RG, Mortensson E, Williams AC. Targeting LGR5 in colorectal cancer: Therapeutic gold or too plastic? Br J Cancer 2018; 118(11): 1410-8.
[http://dx.doi.org/10.1038/s41416-018-0118-6] [PMID: 29844449]
[10]
Xu L, Lin W, Wen L, Li G. Lgr5 in cancer biology: Functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy. Stem Cell Res Ther 2019; 10(1): 219.
[http://dx.doi.org/10.1186/s13287-019-1288-8] [PMID: 31358061]
[11]
Lee HJ, Myung JK, Kim HS, et al. Expression of LGR5 in mammary myoepithelial cells and in triple-negative breast cancers. Sci Rep 2021; 11(1): 17750.
[http://dx.doi.org/10.1038/s41598-021-97351-y] [PMID: 34493772]
[12]
Sato K, Uehara T, Nakajima T, et al. Inverse correlation between PD-L1 expression and LGR5 expression in tumor budding of stage II/III colorectal cancer. Ann Diagn Pathol 2021; 52: 151739.
[http://dx.doi.org/10.1016/j.anndiagpath.2021.151739] [PMID: 33862415]
[13]
Shekarriz R, Montazer F, Alizadeh NR. Overexpression of cancer stem cell marker Lgr5 in colorectal cancer patients and association with clinicopathological findings. Caspian J Intern Med 2019; 10(4): 412-6.
[PMID: 31814939]
[14]
Łukasiewicz S, Czeczelewski M, Forma A, Baj J, Sitarz R, Stanisławek A. Breast cancer—epidemiology, risk factors, classification, prognostic markers, and current treatment strategies—An updated review. Cancers 2021; 13(17): 4287.
[http://dx.doi.org/10.3390/cancers13174287] [PMID: 34503097]
[15]
Azamjah N, Soltan ZY, Zayeri F. Global trend of breast cancer mortality rate: A 25-year study. Asian Pac J Cancer Prev 2019; 20(7): 2015-20.
[http://dx.doi.org/10.31557/APJCP.2019.20.7.2015] [PMID: 31350959]
[16]
Turner KM, Yeo SK, Holm TM, Shaughnessy E, Guan JL. Heterogeneity within molecular subtypes of breast cancer. Am J Physiol Cell Physiol 2021; 321(2): C343-54.
[http://dx.doi.org/10.1152/ajpcell.00109.2021] [PMID: 34191627]
[17]
Johnson KS, Conant EF, Soo MS. Molecular subtypes of breast cancer: A review for breast radiologists. J Breast Imaging 2021; 3(1): 12-24.
[http://dx.doi.org/10.1093/jbi/wbaa110]
[18]
Ghosh S, Javia A, Shetty S, et al. Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches. J Control Release 2021; 337: 27-58.
[http://dx.doi.org/10.1016/j.jconrel.2021.07.014] [PMID: 34273417]
[19]
Garrido CAC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: Improving patient selection for treatment. Cancer Discov 2019; 9(2): 176-98.
[http://dx.doi.org/10.1158/2159-8290.CD-18-1177] [PMID: 30679171]
[20]
Bai X, Ni J, Beretov J, Graham P, Li Y. Cancer stem cell in breast cancer therapeutic resistance. Cancer Treat Rev 2018; 69: 152-63.
[http://dx.doi.org/10.1016/j.ctrv.2018.07.004] [PMID: 30029203]
[21]
Ghasemi F, Sarabi PZ, Athari SS, Esmaeilzadeh A. Therapeutics strategies against cancer stem cell in breast cancer. Int J Biochem Cell Biol 2019; 109: 76-81.
[http://dx.doi.org/10.1016/j.biocel.2019.01.015] [PMID: 30772480]
[22]
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6(7): e1000097.
[http://dx.doi.org/10.1371/journal.pmed.1000097] [PMID: 19621072]
[23]
Downes MJ, Brennan ML, Williams HC, Dean RS. Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS). BMJ Open 2016; 6(12): e011458.
[http://dx.doi.org/10.1136/bmjopen-2016-011458] [PMID: 27932337]
[24]
Sami E, Bogan D, Molinolo A, Koziol J, ElShamy WM. The molecular underpinning of geminin-overexpressing triple-negative breast cancer cells homing specifically to lungs. Cancer Gene Ther 2021; 29(3-4): 304-25.
[PMID: 33723406]
[25]
Ogasawara S, Uehara T, Nakajima T, et al. Correlation of clinicopathological features and LGR5 expression in triple-negative breast cancer. Ann Diagn Pathol 2020; 46: 151491.
[http://dx.doi.org/10.1016/j.anndiagpath.2020.151491] [PMID: 32163872]
[26]
Hagerling C, Owyong M, Sitarama V, et al. LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target. BMC Cancer 2020; 20(1): 542.
[http://dx.doi.org/10.1186/s12885-020-06986-z] [PMID: 32522170]
[27]
Shen R, Wu T, Huang P, Shao Q, Chen M. The clinicopathological significance of ubiquitin-conjugating enzyme E2C, leucine-rich repeated-containing G protein-coupled receptor, WW domain-containing oxidoreductase, and vasculogenic mimicry in invasive breast carcinoma. Medicine 2019; 98(16): e15232.
[http://dx.doi.org/10.1097/MD.0000000000015232] [PMID: 31008954]
[28]
Hou MF, Chen PM, Chu PY. LGR5 overexpression confers poor relapse-free survival in breast cancer patients. BMC Cancer 2018; 18(1): 219.
[http://dx.doi.org/10.1186/s12885-018-4018-1] [PMID: 29471794]
[29]
Yang L, Tang H, Kong Y, et al. LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/β-catenin signaling. Stem Cells 2015; 33(10): 2913-24.
[http://dx.doi.org/10.1002/stem.2083] [PMID: 26086949]
[30]
Zhang X, Powell K, Li L. Breast cancer stem cells: Biomarkers, identification and isolation methods, regulating mechanisms, cellular origin, and beyond. Cancers 2020; 12(12): 3765.
[http://dx.doi.org/10.3390/cancers12123765] [PMID: 33327542]
[31]
Cheng B, Yang G, Jiang R, et al. Cancer stem cell markers predict a poor prognosis in renal cell carcinoma: A meta-analysis. Oncotarget 2016; 7(40): 65862-75.
[http://dx.doi.org/10.18632/oncotarget.11672] [PMID: 27588469]
[32]
Leng Z, Xia Q, Chen J, et al. Lgr5+ CD44+ EpCAM+ strictly defines cancer stem cells in human colorectal cancer. Cell Physiol Biochem 2018; 46(2): 860-72.
[http://dx.doi.org/10.1159/000488743] [PMID: 29627827]
[33]
Fukuma M, Tanese K, Effendi K, et al. Leucine-rich repeat-containing G protein-coupled receptor 5 regulates epithelial cell phenotype and survival of hepatocellular carcinoma cells. Exp Cell Res 2013; 319(3): 113-21.
[http://dx.doi.org/10.1016/j.yexcr.2012.10.011] [PMID: 23127514]
[34]
McClanahan T, Koseoglu S, Smith K, et al. Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol Ther 2006; 5(4): 419-26.
[http://dx.doi.org/10.4161/cbt.5.4.2521] [PMID: 16575208]
[35]
Becker L, Huang Q, Mashimo H. Lgr5, an intestinal stem cell marker, is abnormally expressed in Barrett’s esophagus and esophageal adenocarcinoma. Dis Esophagus 2010; 23(2): 168-74.
[http://dx.doi.org/10.1111/j.1442-2050.2009.00979.x] [PMID: 19549212]
[36]
Wang B, Chen Q, Cao Y, et al. LGR5 is a gastric cancer stem cell marker associated with stemness and the EMT signature genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1. PLoS One 2016; 11(12): e0168904.
[http://dx.doi.org/10.1371/journal.pone.0168904] [PMID: 28033430]
[37]
Wang Z, Zhao T, Zhang S, et al. The Wnt signaling pathway in tumorigenesis, pharmacological targets, and drug development for cancer therapy. Biomark Res 2021; 9(1): 68.
[http://dx.doi.org/10.1186/s40364-021-00323-7] [PMID: 34488905]
[38]
Zhang J, Cai H, Sun L, et al. LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients. J Exp Clin Cancer Res 2018; 37(1): 225.
[http://dx.doi.org/10.1186/s13046-018-0864-6] [PMID: 30208924]
[39]
Sadek SA, Rehim ADM, Fatima S. The role of tumor budding in colorectal adenocarcinoma: Possible involvement of the intestinal cancer stem cell marker Lgr5. Indian J Pathol Microbiol 2020; 63(1): 32-7.
[http://dx.doi.org/10.4103/IJPM.IJPM_154_19] [PMID: 32031119]
[40]
Walker F, Zhang HH, Odorizzi A, Burgess AW. LGR5 is a negative regulator of tumourigenicity, antagonizes Wnt signalling and regulates cell adhesion in colorectal cancer cell lines. PLoS One 2011; 6(7): e22733.
[http://dx.doi.org/10.1371/journal.pone.0022733] [PMID: 21829496]
[41]
DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin 2019; 69(6): 438-51.
[http://dx.doi.org/10.3322/caac.21583] [PMID: 31577379]
[42]
Jiang Y, Li W, He X, Zhang H, Jiang F, Chen Z. Lgr5 expression is a valuable prognostic factor for colorectal cancer: Evidence from a meta-analysis. BMC Cancer 2015; 15(1): 948.
[http://dx.doi.org/10.1186/s12885-015-1985-3] [PMID: 26674601]
[43]
Chen Q, Zhang X, Li WM, Ji YQ, Cao HZ, Zheng P. Prognostic value of LGR5 in colorectal cancer: A meta-analysis. PLoS One 2014; 9(9): e107013.
[http://dx.doi.org/10.1371/journal.pone.0107013] [PMID: 25192390]
[44]
Trejo CL, Luna G, Dravis C, Spike BT, Wahl GM. Lgr5 is a marker for fetal mammary stem cells, but is not essential for stem cell activity or tumorigenesis. NPJ Breast Cancer 2017; 3(1): 16.
[http://dx.doi.org/10.1038/s41523-017-0018-6] [PMID: 28649656]
[45]
Yeung KT, Yang J. Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol 2017; 11(1): 28-39.
[http://dx.doi.org/10.1002/1878-0261.12017] [PMID: 28085222]
[46]
Li F, Song X, Li X, et al. Lgr5 maintains stemness and regulates cell property in nasopharyngeal carcinoma through Wnt/β-catenin signaling pathway. Stem Cell Res 2020; 47: 101916.
[http://dx.doi.org/10.1016/j.scr.2020.101916] [PMID: 32721896]
[47]
Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SA, Miri SR. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis 2021; 8(3): 287-97.
[http://dx.doi.org/10.1016/j.gendis.2020.06.005] [PMID: 33997176]
[48]
Wang W, Nag S, Zhang R. Targeting the NFκB signaling pathways for breast cancer prevention and therapy. Curr Med Chem 2014; 22(2): 264-89.
[http://dx.doi.org/10.2174/0929867321666141106124315] [PMID: 25386819]
[49]
Lai S, Cheng R, Gao D, Chen YG, Deng C. LGR5 constitutively activates NF‐κB signaling to regulate the growth of intestinal crypts. FASEB J 2020; 34(11): 15605-20.
[http://dx.doi.org/10.1096/fj.202001329R] [PMID: 33001511]
[50]
Phung MT, Tin TS, Elwood JM. Prognostic models for breast cancer: A systematic review. BMC Cancer 2019; 19(1): 230.
[http://dx.doi.org/10.1186/s12885-019-5442-6] [PMID: 30871490]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy