Interferon Regulatory Factor-1 Mediates the Proapoptotic but Not Cell Cycle Arrest Effects of the Steroidal Antiestrogen ICI 182,780 (Faslodex, Fulvestrant)

Bouker, Kerrie B.; Skaar, Todd C.; Fernández, David; O’Brien, Keith; Riggins, Rebecca B.; Cao, Deliang; Clarke, Robert

doi:10.1158/0008-5472.can-03-3602

Cited by 71 publications

(84 citation statements)

References 56 publications

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“…The underexpressed set was found to be enriched in TFBSs principally of the interferon regulatory transcription factor (IRF) family (Figure 4a). Notably, IRF1 activity was previously demonstrated to be critical in response to endocrine therapies through promoting apoptosis (Gu et al, 2002;Bouker et al, 2004;Bowie et al, 2004). In contrast, the overexpressed set principally showed enrichment in E2Fs and SP1 TFBSs (Figure 4a).…”

Section: Effect Of 17be2 Through Eramentioning

confidence: 82%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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Section: Effect Of 17be2 Through Eramentioning

confidence: 82%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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“…In models of apoptosis in solid cancer cell lines by chemotherapy, there seems to be a longer time course of apoptosis, and a less marked response than those seen by death-ligands, similar to our model. In one study, doxorubicin has been found to upregulate IRF-1 in ERÀ and ER þ breast cancer cell lines (Bouker et al, 2004), and therefore it is possible that IRF-1 can mediate the ligand-independent FADD/caspase-8-mediated apoptosis seen with certain chemotherapeutics.…”

Section: Irf-1 Induces Ligand-independent Fadd-mediated Apoptosismentioning

confidence: 99%

“…IRF-1 not only induces apoptosis, but is also a necessary mediator of apoptosis for agents against breast cancer including Mullerian inhibiting substance (MIS) (Gupta et al, 2005), faslodex (Bouker et al, 2004), and in E6 expressing HMECs, tamoxifen (Bowie et al, 2004) and reconstituted extracellular matrix (Bowie et al, 2006). Despite the expanding role of IRF-1 in mediating apoptosis by various agents, the mechanism of IRF-1-induced apoptosis has been largely unstudied.…”

Section: Introductionmentioning

confidence: 99%

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

et al. 2007

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Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-c is mediated by IRF-1 and IFN-c, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.

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“…IRF-1 has been implicated to be involved in ICI 182 780 anti-estrogen resistance in breast cancer (Gu et al, 2002). IRF-1 is induced by the estrogen agonist/antagonist, tamoxifen (Tam) and the pure estrogen antagonist, ICI 182 780 (Bouker et al, 2004;Bowie et al, 2004). Taken together, these observations support the role of IRF-1 signaling in mammary gland homeostasis and estrogen/anti-estrogen signaling.…”

Section: Introductionmentioning

confidence: 59%

“…IRF-1 can be induced by type II-IFN (IFN-g) (Romeo et al, 2002) and is known to participate in both p53-dependent and -independent apoptotic signaling (Tamura et al, 1995;Tanaka et al, 1996). Recently, IRF-1 was shown to participate in both type IFN-g and anti-estrogen ICI 182 780 p53-independent apoptotic signaling in human breast cancer cell lines (Bouker et al, 2004;Porta et al, 2005). Taken together, these observations suggest that IRF-1 plays a role in p53-independent apoptotic signaling in mammary epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Interferon regulatory factor-1 regulates reconstituted extracellular matrix (rECM)-mediated apoptosis in human mammary epithelial cells

et al. 2006

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Interactions between extracellular matrix (ECM) and mammary epithelial cells are critical for mammary gland homeostasis and apoptotic signaling. Interferon regulatory factor-1 (IRF-1) is a transcriptional regulator that promotes apoptosis during mammary gland involution and p53-independent apoptosis. We have recently shown that rapid cell surface tamoxifen (Tam) signaling promotes apoptosis in normal human mammary epithelial cells that were acutely damaged by expression of human papillomavirus type-16 E6 protein (*HMEC-E6). Apoptosis was mediated by recruitment of CREB-binding protein (CBP) to the c-activating sequence (GAS) element of the IRF-1 promoter, induction of IRF-1 and caspase-1/-3 activation. Here, we show that growth factor-depleted, reconstituted ECM (rECM), similar to Tam, promotes apoptosis in *HMEC-E6 cells through induction of IRF-1. Apoptosis was temporally associated with recruitment of CBP to the GAS element of the IRF-1 promoter, induction of IRF-1 expression and caspase-1/-3 activation. Small interfering RNA-mediated suppression of IRF-1 protein expression in *HMEC-E6 cells blocked (1) induction of IRF-1, (2) caspase-1/-3 activation and (3) apoptosis. These observations demonstrate that IRF-1 promotes rECM-mediated apoptosis and provide evidence that both rECM and rapid Tam signaling transcriptionally activate IRF-1 through recruitment of CBP to the IRF-1 GAS promoter complex.

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Interferon Regulatory Factor-1 Mediates the Proapoptotic but Not Cell Cycle Arrest Effects of the Steroidal Antiestrogen ICI 182,780 (Faslodex, Fulvestrant)

Abstract: Antiestrogens induce both cytostasis (cell cycle arrest) and apoptosis, but the relationship between these end points and the signaling that regulates their induction are unclear. We have previously implicated the transcription factor and putative tumor suppressor IFN regulatory factor-1 (

Cited by 71 publications

References 56 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

Interferon regulatory factor-1 regulates reconstituted extracellular matrix (rECM)-mediated apoptosis in human mammary epithelial cells

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