Interferon regulatory factor-1 exhibits tumor suppressor activity in breast cancer and partially mediates responsiveness to the antiestrogen ICI 182,780

Interferon Regulatory Factor-1 (IRF-1) is a nuclear transcription factor known to exhibit tumor suppressive effects in several cancers. However, the functional role of IRF-1, if any, in breast cancer is unknown. We show here that IRF-1 is most highly expressed in the non-tumorigenic mammary epithelial cell line A1N4, with a decrease in expression with increasing aggressiveness of the cell line, suggesting a role for IRF-1 in breast cancer. Therefore, we created a dominant negative IRF-1, with respect to its transactivation ability, to definitively ascertain the functional role of IRF-1 in breast cancer. Inhibition of IRF-1 activity, through the use of a dominant negative IRF-1, potentiated the growth, anchorage-dependent colony formation, and tumorigenicity of MCF-7 and T47D breast cancer cell. Further, ectopic expression of IRF-1 attenuated the tumorigenicity of MCF-7 cells in athymic nude mice. Taken together, these data implicate IRF-1 as a tumor suppressor in breast cancer.; In addition to establishing a role for IRF-1 in suppressing tumorigenicity in breast cancer, we provide evidence that this gene partially mediates responsiveness to the clinically useful antiestrogen ICI 182,780 (Faslodex). We demonstrate that the expression, transcriptional activity and hormonal regulation of IRF-1 is altered in antiestrogen resistant cells. Further, MCF-7 and T47D cells stably expressing a dominant negative IRF-1 are less responsive to the growth inhibitory effects of ICI 182,780, through an attenuation of ICI 182,780-induced apoptosis by the dominant negative IRF-1. Taken together this research demonstrates that IRF-1 partially mediates sensitivity to ICI 182,780 providing a novel mechanism for acquired antiestrogen resistance.; Genes that contribute to the altered expression and activity of IRF-1 in antiestrogen resistant cells await further investigation, but may include nucleophosmin and TNF-α. Whether IRF-1 can serve as a prognostic marker for disease progression or predict for responsiveness to antiestrogen therapy remains to be determined. However, the data presented here provide ample evidence that further investigation into the role of IRF-1 in breast cancer and responsiveness to antiestrogens is warranted.