Study of TLR3, TLR4 and TLR9 in Breast Carcinomas and Their Association with Metastasis

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2010 Dec 7

PMID 21129170

Citations 127

Authors

Salome Gonzalez-Reyes

Laura Marin

Lucia Gonzalez

Luis O Gonzalez

Jose M del Casar

Maria L Lamelas

Jose M Gonzalez-Quintana

Francisco J Vizoso

Affiliations

Soon will be listed here.

Abstract

Background: Toll-like receptors (TLRs) have garnered an extraordinary amount of interest in cancer research due to their role in tumor progression. By activating the production of several biological factors, TLRs induce type I interferons and other cytokines, which drive an inflammatory response and activate the adaptive immune system. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in breast cancer.

Methods: The expression levels of TLR3, TLR4 and TLR9 were analyzed on tumors from 74 patients with breast cancer. The analysis was performed by immunohistochemistry.

Results: Samples of carcinomas with recurrence exhibited a significant increase in the mRNA levels of TLR3, TLR4 and TLR9. Tumors showed high expression of TLRs expression levels by cancer cells, especially TLR4 and 9. Nevertheless, a significant percentage of tumors also showed TLR4 expression by mononuclear inflammatory cells (21.6%) and TLR9 expression by fibroblast-like cells (57.5%). Tumors with high TLR3 expression by tumor cell or with high TLR4 expression by mononuclear inflammatory cells were significantly associated with higher probability of metastasis. However, tumours with high TLR9 expression by fibroblast-like cells were associated with low probability of metastasis.

Conclusions: The expression levels of TLR3, TLR4 and TLR9 have clinical interest as indicators of tumor aggressiveness in breast cancer. TLRs may represent therapeutic targets in breast cancer.

Citing Articles

Toll-like receptor 3: a double-edged sword.

Hsieh M, Nishizaki D, Adashek J, Kato S, Kurzrock R Biomark Res. 2025; 13(1):32.

PMID: 39988665 PMC: 11849352. DOI: 10.1186/s40364-025-00739-5.

TLR3 activation mediates partial epithelial-to-mesenchymal transition in human keratinocytes.

Schneider A, Feehan R, Sennett M, Wills C, Garner C, Cong Z Life Sci Alliance. 2024; 7(12).

PMID: 39348939 PMC: 11443013. DOI: 10.26508/lsa.202402777.

Deciphering the role of TLR3 polymorphisms in oral squamous cell carcinoma pathogenesis: A case-control study.

Sharma A, Jaiswal R, Singh S, Asthana P, Tandon A, Shakarwal P J Oral Maxillofac Pathol. 2024; 28(2):232-239.

PMID: 39157834 PMC: 11329090. DOI: 10.4103/jomfp.jomfp_47_24.

Understanding the Role of Toll-Like Receptors 9 in Breast Cancer.

Al-Alem U, Al-Saruri A, Bamahros H, Mahmoud A, Sible E, Hasan U Cancers (Basel). 2024; 16(15).

PMID: 39123407 PMC: 11311448. DOI: 10.3390/cancers16152679.

Toll-like receptors in breast cancer immunity and immunotherapy.

Zhou J, Zhang L, Liu S, DeRubeis D, Zhang D Front Immunol. 2024; 15:1418025.

PMID: 38903515 PMC: 11187004. DOI: 10.3389/fimmu.2024.1418025.

References

Earl T, Nicoud I, PIERCE J, Wright J, Majoras N, Rubin J . Silencing of TLR4 decreases liver tumor burden in a murine model of colorectal metastasis and hepatic steatosis. Ann Surg Oncol. 2009; 16(4):1043-50. DOI: 10.1245/s10434-009-0325-8. View

Smyth M, Godfrey D, Trapani J . A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. 2001; 2(4):293-9. DOI: 10.1038/86297. View

Shojaei H, Oberg H, Juricke M, Marischen L, Kunz M, Mundhenke C . Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells. Cancer Res. 2009; 69(22):8710-7. DOI: 10.1158/0008-5472.CAN-09-1602. View

Medzhitov R, Preston-Hurlburt P, Janeway Jr C . A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997; 388(6640):394-7. DOI: 10.1038/41131. View

Chang H, Sneddon J, Alizadeh A, Sood R, West R, Montgomery K . Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol. 2004; 2(2):E7. PMC: 314300. DOI: 10.1371/journal.pbio.0020007. View

Khatami M . 'Yin and Yang' in inflammation: duality in innate immune cell function and tumorigenesis. Expert Opin Biol Ther. 2008; 8(10):1461-72. DOI: 10.1517/14712598.8.10.1461. View

Flores-Resendiz D, Castellanos-Juarez E, Benitez-Bribiesca L . [Proteases in cancer progression]. Gac Med Mex. 2009; 145(2):131-42. View

Stark J, Wiklund F, Gronberg H, Schumacher F, Sinnott J, Stampfer M . Toll-like receptor signaling pathway variants and prostate cancer mortality. Cancer Epidemiol Biomarkers Prev. 2009; 18(6):1859-63. PMC: 2833418. DOI: 10.1158/1055-9965.EPI-08-0981. View

Murad Y, Clay T, Lyerly H, Morse M . CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy. Expert Opin Biol Ther. 2007; 7(8):1257-66. DOI: 10.1517/14712598.7.8.1257. View

10.

Del Casar J, Gonzalez L, Alvarez E, Junquera S, Marin L, Gonzalez L . Comparative analysis and clinical value of the expression of metalloproteases and their inhibitors by intratumor stromal fibroblasts and those at the invasive front of breast carcinomas. Breast Cancer Res Treat. 2009; 116(1):39-52. DOI: 10.1007/s10549-009-0351-z. View

11.

Pasare C, Medzhitov R . Toll-like receptors and acquired immunity. Semin Immunol. 2004; 16(1):23-6. DOI: 10.1016/j.smim.2003.10.006. View

12.

Stanley M, Pett M, Coleman N . HPV: from infection to cancer. Biochem Soc Trans. 2007; 35(Pt 6):1456-60. DOI: 10.1042/BST0351456. View

13.

Liu N, Lapcevich R, Underhill C, Han Z, Gao F, SWARTZ G . Metastatin: a hyaluronan-binding complex from cartilage that inhibits tumor growth. Cancer Res. 2001; 61(3):1022-8. View

14.

Berger R, Fiegl H, Goebel G, Obexer P, Ausserlechner M, Doppler W . Toll-like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors. Cancer Sci. 2010; 101(4):1059-66. PMC: 3188854. DOI: 10.1111/j.1349-7006.2010.01491.x. View

15.

Inoue J, Gohda J, Akiyama T, Semba K . NF-kappaB activation in development and progression of cancer. Cancer Sci. 2007; 98(3):268-74. PMC: 11158158. DOI: 10.1111/j.1349-7006.2007.00389.x. View

16.

Khatami M . Developmental phases of inflammation-induced massive lymphoid hyperplasia and extensive changes in epithelium in an experimental model of allergy: implications for a direct link between inflammation and carcinogenesis. Am J Ther. 2005; 12(2):117-26. DOI: 10.1097/01.mjt.0000143699.91156.21. View

17.

Huang B, Zhao J, Li H, He K, Chen Y, Chen S . Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005; 65(12):5009-14. DOI: 10.1158/0008-5472.CAN-05-0784. View

18.

Salaun B, Coste I, Rissoan M, Lebecque S, Renno T . TLR3 can directly trigger apoptosis in human cancer cells. J Immunol. 2006; 176(8):4894-901. DOI: 10.4049/jimmunol.176.8.4894. View

19.

Burnet M . Cancer; a biological approach. I. The processes of control. Br Med J. 1957; 1(5022):779-86. PMC: 1973174. DOI: 10.1136/bmj.1.5022.779. View

20.

Chekhun V . Stroma -- regulator of cancer cell progression. Exp Oncol. 2009; 31(3):126. View