Functional Polymorphisms of FAS and FASL Gene and Risk of Breast Cancer – Pilot Study of 134 Cases

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Abstract

Fas/Fas ligand (FasL) system is one of the key apoptotic signaling entities in the extrinsic apoptotic pathway. De-regulation of this pathway, i.e. by mutations may prevent the immune system from the removal of newly-formed tumor cells, and thus lead to tumor formation. The present study investigated the association between −1377 G/A (rs2234767) and −670 A/G (rs1800682) polymorphisms in Fas as well as single nucleotide polymorphisms INV2nt −124 A/G (rs5030772) and −844 C/T (rs763110) in FasL in a sample of Iranian patients with breast cancer. This case-control study was done on 134 breast cancer patients and 152 normal women. Genomic DNA was extracted from whole blood samples. The polymorphisms were determined by using tetra-ARMS-PCR method. There was no significant difference in the genotype distribution of FAS rs2234767 polymorphism between cases and controls. FAS rs1800682, FASL rs5030772, and FASL rs763110 genotypes showed significant associations with an increasing risk of breast cancer (odds ratio OR = 3.18, P = 0.019; OR = 5.08, P = 0.012; OR = 2.40, P = 0.024, respectively). In conclusion, FAS rs2234767 was not associated with breast cancer risk. Though, FAS rs1800682, FASL rs5030772, and FASL rs763110 polymorphisms were associated with the risk of breast cancer in the examined population.

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The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand

GC O’Sullivan, F Shanahan, JK Collins … (1996)

Tumors escape immunological rejection by a diversity of mechanisms. In this report, we demonstrate that the colon cancer cell SW620 expresses functional Fas ligand (FasL), the triggering agent of Fas receptor (FasR)-mediated apoptosis within the immune system. FasL mRNA and cell surface FasL were detected in SW620 cells using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. We show that SW620 kills Jurkat T cells in a Fas-mediated manner. FasR-specific antisense oligonucleotide treatment, which transiently inhibited FasR expression, completely protected Jurkat cells from killing by SW620. FasL-specific antisense oligonucleotide treatment of SW620 inhibited its Jurkat-killing activity. FasL has recently been established as a mediator of immune privilege in mouse retina and testis. Our finding that colon cancer cells express functional FasL suggests it may play an analogous role in bestowing immune privilege on human tumors. HT29 and SW620 colon cancer cells were found to express FasR mRNA and cell surface FasR using RT-PCR and immunofluorescence flow cytometry, respectively. However, neither of these cells underwent apoptosis after treatment by the anti-FasR agonistic monoclonal antibody CH11. Our results therefore suggest a Fas counterattack model for immune escape in colon cancer, whereby the cancer cells resist Fas-mediated T cell cytotoxicity but express functional FasL, an apoptotic death signal to which activated T cells are inherently sensitive.

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Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis.

P Baeuerle, Mark Fiers, L Penning … (1995)

The Fas/APO-1 receptor is one of the major regulators of apoptosis. We report here that Fas/APO-1-mediated apoptosis requires the activation of a new class of cysteine proteases, including interleukin-1 beta-converting enzyme (ICE), which are homologous to the product of the Caenorhabditis elegans cell-death gene ced-3 (refs 11, 12). Triggering of Fas/APO-1 rapidly stimulated the proteolytic activity of ICE. Overexpression of ICE, achieved by electroporation and microinjection, strongly potentiated Fas/APO-1-mediated cell death. In addition, inhibition of ICE activity by protease inhibitors, as well as by transient expression of the pox virus-derived serpin inhibitor CrmA or an antisense ICE construct, substantially suppressed Fas/APO-1-triggered cell death. We conclude that activation of ICE or an ICE-related protease is a critical event in Fas/APO-1-mediated cell death.

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Apoptosis and epithelial injury in the lungs.

N Hagimoto, Morio Nakamura, Kathryn Martin … (2004)

Epithelial injury is a critical event in the development of acute lung injury, but the mechanisms that cause death of the alveolar epithelium are not completely understood. Epithelial death occurs by necrosis and apoptosis; more information is needed about the balance between these two types of cell death in the lungs. Direct epithelial necrosis probably occurs in response to bacterial exotoxins and over-distension of alveolar units by mechanical ventilation. Apoptosis is a regulated form of cell death that is mediated by membrane death receptors and direct mitochondrial injury. Apoptosis pathways are activated in the lungs of patients with acute lung injury, in part by activation of the membrane Fas death receptor by soluble Fas ligand (sFasL), which accumulates in biologically active form at the onset of lung injury. Accumulating evidence in humans and experimental models links sFasL and Fas pathway with lung epithelial injury and fibrosis. New strategies to inhibit Fas-mediated epithelial apoptosis need to be developed in order to develop new ways to preserve epithelial function in patients who develop acute lung injury.

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Author and article information

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Kin Mang Lau: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 11 January 2013

Volume: 8

Issue: 1

Electronic Location Identifier: e53075

Affiliations

[1 ]Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran

[2 ]Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran

[3 ]Department of Internal Medicine, School of Medicine, Zahedan University of Medical Science, Zahedan, Iran

[4 ]Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada

[5 ]Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

[6 ]Genetic of Non Communicable Disease Research Center, Zahedan University of Medical Science, Zahedan, Iran

[7 ]Department of Clinical and Experimental Medicine, Integrative Regenerative Med. Center (IGEN), Division of Cell Biology, Linköping University, Linköping, Sweden

[8 ]Department of Biology, Faculty of Sciences, University of Tunis, Tunis, Tunisia

[9 ]BioApplications Enterprises, Winnipeg, Manitoba, Canada

The Chinese University of Hong Kong, Hong Kong

Author notes

* E-mail: marek.los@ 123456liu.se

Competing Interests: ML is a director of BioApplications Enterprise, a company aimed at transferring scientific discoveries from academia to industry. There are no patents, products in development or marketed products to declare. This fact does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Prepared figure panels explaining the methodology: WC MVJ. Conceived and designed the experiments: MH AF SG MT. Performed the experiments: AF MT. Analyzed the data: MH SG WC MVJ ML. Contributed reagents/materials/analysis tools: AF EEN FA MAM MT. Wrote the paper: MH SG WC MVJ ML.

Article

Publisher ID: PONE-D-12-18666

DOI: 10.1371/journal.pone.0053075

PMC ID: 3543397

PubMed ID: 23326385

SO-VID: c596a4b0-7ec7-4954-98ed-63455cf02c6d

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 June 2012

Date accepted : 23 November 2012

Page count

Pages: 9

Funding

SG was supported by Parker B. Francis Fellowship in Respiratory Disease. ML, WC, and MVJ kindly acknowledge the core/startup support from Linköping University, from Integrative Regenerative Medicine Center (IGEN), and from Cancerfonden (CAN 2011/521). No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Functional Polymorphisms of FAS and FASL Gene and Risk of Breast Cancer – Pilot Study of 134 Cases

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Most cited references 47

The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand

Requirement of an ICE/CED-3 protease for Fas/APO-1-mediated apoptosis.

Apoptosis and epithelial injury in the lungs.

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