Interferon Regulatory Factor-1 and -2 Expression in Human Melanoma Specimens

Lowney, Jennifer K.; Boucher, Leslie D.; Swanson, Paul E.; Doherty, Gerard M.

doi:10.1007/s10434-999-0604-4

Cited by 27 publications

(22 citation statements)

References 18 publications

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“…20 In that article, we reported that IRF-1 expression was most common in early forms of melanoma (thin lesions, lower AJCC stage) and less common in more advanced lesions. IRF-2 staining did not follow any clear pattern in that small study.…”

Section: Discussionmentioning

confidence: 99%

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Interferon Regulatory Factor Expression in Human Breast Cancer

Doherty¹,

Boucher²,

Sorenson³

et al. 2001

Annals of Surgery

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ObjectiveTo investigate the expression of interferon regulatory factors 1 and 2 (IRF-1 and IRF-2) in human breast cancer. Summary Background DataInterferon regulatory factors 1 and 2 are transcription factors in the interferon gamma signal transduction pathway. IRF-1 acts as the effector arm of the interferon gamma response; IRF-2 binds to the same DNA consensus sequence and opposes IRF-1 activity. Previous work in the authors' laboratory has shown the tumor suppressor activity of IRF-1 expression and the oncogenic effect of IRF-2 in human and murine tumor models, including human breast cancer cell lines. The authors' hypothesis is that this pathway is involved in human tumor development, and alterations in the expression of IRF-1 and IRF-2 may occur in breast cancer tissue compared with normal breast tissue, and between more and less differentiated breast cancers. MethodsFormalin-fixed paraffin-embedded human archival tissue specimens were obtained from 33 patients with pure ductal carcinoma in situ (DCIS) and 49 women with invasive ductal cancer. Adjacent areas of normal breast tissue were assayed in 31 women. These specimens were stained with polyclonal IRF-1 and IRF-2 antibodies using an avidin-biotin-peroxidase complex technique after epitope retrieval. ResultsMost normal breast tissue showed expression of IRF-1 and no expression of IRF-2 by immunohistochemistry. High-grade DCIS or node-positive invasive ductal cancers were less likely to express the tumor suppressor IRF-1 than normal tissue. More strikingly, high-grade DCIS and invasive ductal cancers were much more likely to express the oncogenic IRF-2 protein than was normal tissue. ConclusionsExpression of IRF-1 and IRF-2 is altered in human breast cancer compared with normal adjacent tissue. The loss of IRF-1 expression is consistent with tumor suppressor loss and the development of IRF-2 expression with oncogenic activation. These data support the hypothesis that this pathway is involved in human breast oncogenesis, which warrants further investigation regarding prognostic and therapeutic implications.Neoplasia occurs as a result of cellular changes that perturb normal balances of cell growth and cell death. As the pathways regulating growth control have become understood, alterations in these pathways have been identified that characterize breast cancer and can help to select therapies for patients. Examples of measurements that have been used to describe breast cancer growth include DNA ploidy, S-phase fraction, p53 status, her2/neu expression, and estrogen receptor expression. In this study, we investigated two additional factors using immunohistochemical techniques that may allow clinical assessment of the intactness of interferon gamma (IFN-␥)-based immunity in individual host-tumor relationships.Interferon gamma is a cytokine, made by T cells and natural killer cells, that has a variety of effects on different cells. Among its actions are antitumor effects, although these have been difficult to translate into clinical use. The

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Section: Discussionmentioning

confidence: 99%

“…To date, the only study of IRF-1 and IRF-2 in human solid tumors is our study of IRF-1 and IRF-2 expression in archival melanoma samples. 20 However, there have been no studies before this one that assess the expression of IRF-1 and IRF-2 in human breast cancer tissue.…”

Section: Discussionmentioning

confidence: 99%

Interferon Regulatory Factor Expression in Human Breast Cancer

Doherty¹,

Boucher²,

Sorenson³

et al. 2001

Annals of Surgery

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“…Similarly, embryonic fibroblasts from IRF-1 knockout mice, but not wild-type mice, were transformed by forced expression of mutant c-Ha-ras oncogene (13). The loss of IRF-1 expression and gain of IRF-2 expression in human melanoma and breast cancer cells have been associated with their more malignant phenotype (14,15). In addition, incremental loss of IRF-1 expression paralleled the advancement of hepatic and endometrial cancers (16,17).…”

Section: Introductionmentioning

confidence: 99%

Involvement of IFN Regulatory Factor (IRF)-1 and IRF-2 in the Formation and Progression of Human Esophageal Cancers

et al. 2007

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IFN regulatory factor (IRF)-1 and IRF-2 are generally regarded as a tumor suppressor and an oncoprotein, respectively. However, little is known about their expression and function in esophageal squamous cell carcinomas (ESCC). In our present work, IRF-1 expression was decreased and IRF-2 expression was increased in ESCCs compared with matched normal esophageal tissues. Moreover, statistical data indicated that IRF-2 expression was tightly correlated with progression of ESCCs. As expected, overexpression of either IRF-1 or IRF-2 in an ESCC cell line resulted in either suppression or enhancement of cell growth, respectively. Also, proliferationand apoptosis-related molecules (p21 WAF1/CIP1 , cyclin-D1, Bcl-2, and histone H4) were regulated by IRF-1 and IRF-2.

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“…10 In human melanoma and breast cancer, loss of IRF-1 and gain of IRF-2 expression was associated with a more malignant phenotype. 11,12 In various ovarian cancer cell lines growth suppression and apoptotic index upon IFN-g exposure were highly related to the inducibility of IRF-1 in the respective cell lines. Moreover, in PA-1 cells, ligand-independent apoptosis was strongly induced when IRF-1 was transiently over-expressed.…”

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Intratumoral interferon regulatory factor (IRF)‐1 but not IRF‐2 is of relevance in predicting patient outcome in ovarian cancer

Zeimet

Reimer

Wolf

et al. 2009

Intl Journal of Cancer

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IRF‐1 and IRF‐2 expression was determined by real‐time PCR in 138 ovarian cancer samples and 30 healthy ovarian biopsies and was correlated with the expression of other relevant immunologic parameters and common clinicopathologic variables. Regulation of IRF‐1 and IRF‐2 was evaluated by cytokine treatment of various ovarian cancer cell lines, human peritoneal mesothelial cells and ovarian surface epithelium. IRF‐1 but not IRF‐2 was constitutively over‐expressed in 5 of 7 ovarian cancer cell lines. Both IRFs were inducible with IFN‐γ and to a lesser extent with IL‐1 or TNF‐α, but not with IL‐6. Epidermal growth factor (EGF) treatment down‐regulated both IRFs. In ovarian cancer samples only IRF‐1, but not IRF‐2 mRNA, was up‐regulated when compared with healthy ovarian tissue. IRF‐1 but not IRF‐2 expression was significantly associated with interferon (IFN)‐γ and forkhead box P3 (FoxP3). In univariate survival analysis, strong expression of IRF‐1 and IRF‐2 predicted improved disease‐free survival (DFS) and overall survival (OS). In Cox regression analyses, IRF‐1 retained independent prognostic significance for DFS and OS and IFN‐γ for OS. In contrast to other solid tumors, IRF‐2 expression cannot be regarded as a classic oncoprotein associated with poor prognosis in ovarian cancer. Of the immunologic parameters investigated, intratumoral IRF‐1 expression is the most powerful independent predictor of a favorable clinical outcome. © 2008 Wiley‐Liss, Inc.

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Interferon Regulatory Factor-1 and -2 Expression in Human Melanoma Specimens

Cited by 27 publications

References 18 publications

Interferon Regulatory Factor Expression in Human Breast Cancer

Interferon Regulatory Factor Expression in Human Breast Cancer

Involvement of IFN Regulatory Factor (IRF)-1 and IRF-2 in the Formation and Progression of Human Esophageal Cancers

Intratumoral interferon regulatory factor (IRF)‐1 but not IRF‐2 is of relevance in predicting patient outcome in ovarian cancer

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