The Role of Interferon Regulatory Factor-1 (IRF1) in Overcoming Antiestrogen Resistance in the Treatment of Breast Cancer

Abstract

Resistance to endocrine therapy is common among breast cancer patients with estrogen receptor alpha-positive (ER+) tumors and limits the success of this therapeutic strategy. While the mechanisms that regulate endocrine responsiveness and cell fate are not fully understood, interferon regulatory factor-1 (IRF1) is strongly implicated as a key regulatory node in the underlying signaling network. IRF1 is a tumor suppressor that mediates cell fate by facilitating apoptosis and can do so with or without functional p53. Expression of IRF1 is downregulated in endocrine-resistant breast cancer cells, protecting these cells from IRF1-induced inhibition of proliferation and/or induction of cell death. Nonetheless, when IRF1 expression is induced following IFNγ treatment, antiestrogen sensitivity is restored by a process that includes the inhibition of prosurvival BCL2 family members and caspase activation. These data suggest that a combination of endocrine therapy and compounds that effectively induce IRF1 expression may be useful for the treatment of many ER+ breast cancers. By understanding IRF1 signaling in the context of endocrine responsiveness, we may be able to develop novel therapeutic strategies and better predict how patients will respond to endocrine therapy.

Figure 1

Domain structures of IRF1 and IRF2. IRF1 and IRF2 are composed of a DNA-binding domain (DBD; N-terminus) and a regulatory domain (C-terminus). The DBD is characterized by five tryptophan residues each separated by 10–18 amino acids. IRF1 and IRF2 also contain an IRF association domain (IAD). For IRF1, activity depends on phosphorylation, whereas IRF2 contains a repression domain (red). The size of each IRF1 (in amino acids; aa) is also indicated. C: carboxyl terminus; N: amino terminus.

Figure 2

Putative IRF1-driven cell fate through BCL2 family members, BIRC5, and caspases.