Article

Altered Expression of FAS System Is Related to Adverse Clinical Outcome in Stage I-II Breast Cancer Patients Treated with Adjuvant Anthracycline-Based Chemotherapy

Regina Elena Cancer Institute, Rome, Italy, and University of Camerino, Camerino, Italy.
Clinical Cancer Research (Impact Factor: 8.72). 02/2004; 10(4):1360-5. DOI: 10.1158/1078-0432.CCR-1092-03
Source: PubMed

ABSTRACT

To determine the prognostic value of Fas receptor and Fas ligand (FasL) as apoptosis-related biomarkers in the context of chemoresponsiveness in breast cancer (BC) patients submitted to anthracycline-based adjuvant therapy.
Fas and FasL were investigated by immunohistochemistry in surgical samples collected from 167 stage I-IIa-b BC patients enrolled in a prospective clinical trial using epirubicin plus cyclophosphamide in the adjuvant setting.
Fas and FasL were significantly associated with tumor stage (P < 0.0001). Multivariate analysis indicated that stage, loss of Fas (relative risk, 8.5 and 9.12; P < 0.0001) and FasL up-regulation (relative risk, 2.38 and 2.88; P = 0.01) were independent prognostic variables influencing both disease-free survival (DFS) and overall survival (OS). A Cox analysis using a four-category Fas/FasL phenotype (+/-, +/+, -/+, -/-) as a stratification factor evidenced a highly positive association between Fas/FasL phenotype and the cumulative hazard of relapse and death in the entire series of patients. We also estimated the DFS and OS for different combinations of the pathological-tumor-node-metastasis (TNM) stage and Fas/FasL by using the K sample log-rank exact test demonstrating that significantly shorter DFS and OS were observed in Fas-negative and FasL-positive patients in both stage I-IIa and IIb.
Data presented herein demonstrated that, according to a number of in vitro studies, the prognosis for BC patients receiving adjuvant anthracycline-based chemotherapy strongly depends on the Fas/FasL status. Therefore, a concomitant altered pattern of Fas/FasL expression seems to configure an aggressive tumor phenotype linked to disease progression.

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    • "It was revealed that the tumor expression of FasL, inducing the apoptosis of CTLs, might enable the neoplasm to evade immune destruction by these cytotoxic cells [5]. The detection of FasL and its mRNA in the variety of human malignancies with different histogenesis supports the concept of FasL-mediated immune escape of the tumor cells [6–14]. In some cases, FasL and its mRNA were detected more frequently in tumor metastases than in primary tumors [15]. "
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    ABSTRACT: Fas and its ligand (FasL) are known to play a crucial role in the genetically controlled mechanism of cell death, and their deregulation in cancer cells is involved in the immune escape of the tumor. The aim of this review is to analyze the current knowledge on the prognostic value of Fas/FasL in breast cancer patients. Both the results of other authors and our own experiences indicate that the lack of Fas ligand, and particularly Fas, is related to a significantly worse prognosis. It probably results from the resistance of Fas-deficient breast tumors to the mechanisms of apoptosis. On the other hand, some results suggest that the Fas/FasL-dependent mechanisms of tumor spread may be different for various target tissues. The expression of the Fas/Fas-ligand system has potential prognostic application in view of current knowledge, and consequently should be considered as an additional prognostic factor in breast cancer patients.
    Full-text · Article · Apr 2013 · Contemporary Oncology / Wspólczesna Onkologia
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    • "In breast cancer, increased BCL2 expression has been associated with a favourable prognosis after treatment with chemotherapy and endocrine therapy (Fitzgibbons et al., 2000), while decreased BAX expression has been linked to poor clinical outcome (Schorr et al., 1999). In addition, prognosis for breast cancer patients receiving adjuvant anthracycline-based chemotherapy strongly depends on the Fas/FasL status (Botti, 2004). It has also been suggested that plasma levels of sFas might be a valuable clinical prognostic factor in predicting outcome for patients with metastatic breast cancer undergoing high-dose chemotherapy treatment (Bewick et al., 2001). "
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    ABSTRACT: Many members of BCL2 (Bcl-2) apoptosis-related genes were found to be differentially expressed in various malignancies and were proposed as prognostic cancer biomarkers. Recently, a new member of the BCL2 gene family, BCL2L12, was cloned and was found to be expressed in mammary gland. In the present study, 55 specimens from patients with, histologically confirmed, epithelial breast carcinoma were analyzed for BCL2 and BCL2L12 gene expression by RT-PCR. Increased expression of BCL2 gene was found in patients belonging to the age groups <45 or >55 years, as well as in estrogen receptors (ER)-positive patients and in BCL2L12-positive tumors. In addition, BCL2 or BCL2L12-positive patients were found to be almost four times less likely to relapse or die in comparison to BCL2 or BCL2L12-negative patients, respectively. Multivariate analysis revealed that BCL2 and BCL2L12 might be used as independent prognostic biomarkers in breast cancer.
    Full-text · Article · Apr 2007 · Cancer Letters
    • "In breast cancer, increased BCL2 expression has been associated with a favourable prognosis after treatment with chemotherapy and endocrine therapy (Fitzgibbons et al., 2000), while decreased BAX expression has been linked to poor clinical outcome (Schorr et al., 1999). In addition, prognosis for breast cancer patients receiving adjuvant anthracycline-based chemotherapy strongly depends on the Fas/FasL status (Botti, 2004). It has also been suggested that plasma levels of sFas might be a valuable clinical prognostic factor in predicting outcome for patients with metastatic breast cancer undergoing high-dose chemotherapy treatment (Bewick et al., 2001). "
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    ABSTRACT: We studied alterations in the mRNA expression levels of BCL2 (Bcl-2), BCL2L12, BAX, FAS and CASPASE-9 genes in the MCF-7 breast cancer cell line in response to treatment with two anticancer drugs. Cell toxicity was evaluated by the MTT method, trypan blue staining and DNA laddering, whereas the expression levels of the apoptosis-related genes were analysed by RT-PCR using gene-specific primers. In the case of etoposide, down-regulation of the BCL2L12-A gene variant and of CASPASE-9, as well as upregulation of BAX, was observed, whereas treatment of MCF-7 cells with taxol led to down-regulation of the mRNA levels of all genes examined. Our results support the idea that after long-term clinical studies, mRNA expression analysis of BCL2L12 and other members of the BCL2 gene family may serve as useful molecular markers predicting chemotherapy response in breast cancer.
    No preview · Article · Sep 2006 · Biological Chemistry
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