Interferon Regulatory Factor Expression in Human Breast Cancer

Abstract

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

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

“…Furthermore, statistical data indicated that IRF-2 expression was tightly correlated with disease progression in esophageal cancer. 16 Moreover, besides the association between high-level IRF-2 expression and improved survival in univariate analyses, other of our findings argue against an oncogenic role of IRF-2 in ovarian cancer: (i) in contrast to other solid tumors such as diffusely infiltrating astrocytomas, breast and as already mentioned esophageal cancers, 16,18,19 the expression of IRF-2 was not found to be upregulated in either ovarian cancer tissue or established ovarian cancer cell lines, (ii) significantly higher levels of IRF-2 mRNA were found in early-stage when compared with advanced-stage ovarian cancers, and (iii) IRF-2 expression was inversely related to residual disease after primary debulking surgery. Concerning the latter point, there is excellent evidence to show that ovarian cancers, whose complete surgical clearance is impossible at primary surgery, exhibit a more aggressive phenotype with a completely different molecular signature than do cancers allowing optimal cytoreduction.…”

Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells

“…This observation suggests that the loss of BRCA1 may facilitate the disruption of the IFN response. IFNregulatory proteins such as IRF-1, STAT1, and ISG12 are dysregulated during breast carcinogenesis (Rasmussen et al, 1993;Watson and Miller, 1995;Doherty et al, 2001) and IFN exhibits cross-talk with estrogen and retinoid signaling (Kolla et al, 1996;Widschwendter et al, 1996;Bjornstrom and Sjoberg, 2002).…”

“…Recent reports have highlighted the ability of IRF-1 to mediate growth arrest and apoptosis in breast cancer cell lines (Kim et al, 2002(Kim et al, , 2004Hoshiya et al, 2003). In addition, evidence suggests that IRF-1 plays a role in mammary homeostasis, as IRF-1 is critical for mammary gland involution and loss of expression of IRF-1 is an early event in mammary carcinogenesis (Doherty et al, 2001). In this study, IRF-1 expression was induced by 60 min treatment with 1.0 mM Tam (Figure 2).…”

“…More recently, IRF-1 has been shown to be a tumor suppressor and critical for mammary gland involution (Yim et al, 1997;Nozawa et al, 1999;Hoshiya et al, 2003;Kim et al, 2004). Studies have also shown that IRF-1 expression is lowered or the gene is mutated in multiple cancers, including breast cancer (Doherty et al, 2001;Tzoanopoulos et al, 2002).…”

Central role of interferon regulatory factor‐1 (IRF‐1) in controlling retinoic acid inducible gene‐I (RIG‐I) expression

“…The loss of IRF-1 allele has also been documented in esophageal and gastric cancers Tamura et al, 1996). IRF-1 expression is lost in human breast cancer when compared to adjacent normal tissue suggesting its involvement in mammary carcinogenesis (Doherty et al, 2001).…”