IFNγ Restores Breast Cancer Sensitivity to Fulvestrant by Regulating STAT1, IFN Regulatory Factor 1, NF-κB, BCL2 Family Members, and Signaling to Caspase-Dependent Apoptosis

Abstract

Antiestrogens are effective therapies for the management of many estrogen receptor-α (ER)-positive breast cancers. Nonetheless, both de novo and acquired resistance occur and remain major problems in the clinical setting. IFNγ is an inflammatory cytokine that induces the expression and function of IFN regulatory factor 1 (IRF1), a tumor suppressor gene that can increase antiestrogen responsiveness. We show that IFNγ, but not IFNα, IFNβ, or fulvestrant (ICI; ICI 182,780; Faslodex), induces IRF1 expression in antiestrogen-resistant MCF7/LCC9 and LY2 cells. Moreover, IFNγ restores the responsiveness of these cells to fulvestrant. Increased IRF1 activation suppresses NF-κB p65 (RELA) activity, inhibits the expression of prosurvival (BCL2, BCL-W), and induces the expression of proapoptotic members (BAK, mitochondrial BAX) of the BCL2 family. This molecular signaling is associated with the activation of signal transducer and activator of transcription 1 and leads to increased mitochondrial membrane permeability; activation of caspase-7 (CASP7), CASP8, and CASP9; and induction of apoptosis but not autophagy. Whereas antiestrogen-resistant cells are capable of inducing autophagy through IFN-mediated signaling, their ability to do so through antiestrogen-regulated signaling is lost. The abilities of IFNγ to activate CASP8, induce apoptosis, and restore antiestrogen sensitivity are prevented by siRNA targeting IRF1, whereas transient overexpression of IRF1 mimics the effects of IFNγ treatment. These observations support the exploration of clinical trials combining antiestrogens and compounds that can induce IRF1, such as IFNγ, for the treatment of some ER-positive breast cancers. Mol Cancer Ther; 9(5); 1274-85. ©2010 AACR.

STAT1 is phosphorylated and downregulated by the oncogenic tyrosine kinase NPM-ALK in ALK-positive anaplastic large-cell lymphoma

“…[28][29][30][31][32] It is believed that STAT1 exerts its tumor suppressor effects by modulating the transcription of a host of proapoptotic and antiproliferative genes, 1,37 such as IRF-1, 23 caspases, 37,38 members of the death receptor family (iNOS, Fas/FasL) and tumor necrosis factor-related apoptosis ligand (TRAIL), [39][40][41][42] Bcl-xL, and Bcl-2. 43,44 Nonetheless, there is evidence suggesting that STAT1 may be oncogenic in specific experimental models and/or cell types, as highlighted in a recent review article. 4 For instance, it was found that STAT1-deficient mice are protected from developing leukemia.…”

IRF-1 inhibits NF-κB activity, suppresses TRAF2 and cIAP1 and induces breast cancer cell specific growth inhibition

“…61 The transcriptional activity of NF-kB p65 is further reduced when breast cancer cells are treated with both IFN-g and the steroidal antiestrogen fulvestrant ICI. 61 IRF-1 was also expressed in the spontaneously immortalized nonmalignant human breast cell line, MCF-10F, cultured with TNF-a, IFN-g, and the combination of TNF-a and IFN-g. In contrast to the human breast cancer cells, however, a change in the expression of NF-kB p65 in the nuclear fraction was not observed in this nonmalignant human breast cell line.…”

Tumor-induced thymic atrophy: Alteration in interferons and Jak/Stats signaling pathways

“…IFN-Á has numerous effects on hematopoietic and tumor cells (19,30,31). One of the consequences of IFN-Á treatments is the induction of apoptosis (20,32). Moreover, Lester et al (33) showed that an ever greater augmentation of IFN-Á production could be caused by neutralization of IL-10 activity.…”