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

Yanxia Ning, Rebecca B. Riggins, Jennifer E. Mulla, Haniee Chung, Alan Zwart, Robert Clarke

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1274-1285
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number5
DOIs
StatePublished - May 1 2010
Externally publishedYes

Fingerprint

Estrogen Receptor Modulators
Caspases
Apoptosis
Breast Neoplasms
Aptitude
Autophagy
Estrogen Receptors
STAT1 Transcription Factor
Caspase 7
Mitochondrial Membranes
fulvestrant
Tumor Suppressor Genes
Small Interfering RNA
Permeability
Clinical Trials
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Ning, Yanxia; Riggins, Rebecca B.; Mulla, Jennifer E.; Chung, Haniee; Zwart, Alan; Clarke, Robert.

In: Molecular Cancer Therapeutics, Vol. 9, No. 5, 01.05.2010, p. 1274-1285.

Research output: Contribution to journalArticle

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