Schematic diagram depicting the proposed mechanism of ISG expression in AI-resistant MCF-7:5C cells. ER-positive breast cancers are dependent on estrogen for survival and growth and when these cancer cells are deprived of estrogen they tend to die. Long term, however, some breast cancer cells develop strategies to allow them to survive and grow in an estrogen-depleted environment. In our working model, we propose that long term estrogen deprivation of ERα positive breast cancer cells elicits a stress response in the cell which can possibly result in increased expression and activation of IRF-7, a known stress response gene. The activated IRF-7 enters the nucleus and binds the IFNα promoter at the IRF binding-element (IRFE) and ISRE sites, resulting in IFNα production and secretion from the cell. IFNα then binds to its cell surface receptor IFNAR1/2 which initiates JAK phosphorylation of the STAT proteins and association with IRF-9, forming the activated ISGF3 complex (p-ISGF3). The BAF complex remodels the chromatin around prospective ISGs and p-ISGF3 is imported into the nucleus where it binds to the exposed ISRE sites in ISG promoters. This results in the sustained/constitutive overexpression of numerous ISGs including IFITM1 and IRF-7, which initiates further IFNα production and thus provides autocrine cytokine signaling, reinforcing the production and accumulation of ISGs. The ISGs are pro-survival and so facilitate cell survival and proliferation under the stressful (estrogen depleted) conditions. Loss of expression of the ISGs reduces the ability of the resistant cells to survive in an estrogen-depleted environment thus causing them to die. AI, aromatase inhibitor; ER, estrogen receptor; IFITM1, interferon induced transmembrane protein1; IRF-7, IFN regulatory factor 7; ISGs, interferon stimulated genes; ISREs, IFN-stimulated response elements; JAK, Janus kinase 1 and 2; STAT, Signal transducer and activator of transcription.