title: Interferon regulatory factor-1 signaling regulates the switch between autophagy and apoptosis to determine breast cancer cell fate.
abstract: Interferon regulatory factor-1 (IRF1) is a tumor suppressor that regulates cell fate in several cell types. Here, we report an inverse correlation in expression of nuclear IRF1 and the autophagy regulator ATG7 in human breast cancer cells that directly affects their cell fate. In mice harboring mutant Atg7, nuclear IRF1 was increased in mammary tumors, spleen, and kidney. Mechanistic investigations identified ATG7 and the cell death modulator beclin-1 (BECN1) as negative regulators of IRF1. Silencing ATG7 or BECN1 caused estrogen receptor-α to exit the nucleus at the time when IRF1 nuclear localization occurred. Conversely, silencing IRF1 promoted autophagy by increasing BECN1 and blunting IGF1 receptor and mTOR survival signaling. Loss of IRF1 promoted resistance to antiestrogens, whereas combined silencing of ATG7 and IRF1 restored sensitivity to these agents. Using a mathematical model to prompt signaling hypotheses, we developed evidence that ATG7 silencing could resensitize IRF1-attenuated cells to apoptosis through mechanisms that involve other estrogen-regulated genes. Overall, our work shows how inhibiting the autophagy proteins ATG7 and BECN1 can regulate IRF1-dependent and -independent signaling pathways in ways that engender a new therapeutic strategy to attack breast cancer.
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Schwartz-Roberts
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Cook
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Ayesha N
authors.initials: AN
authors.lastname: Shajahan-Haq
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Margaret
authors.initials: M
authors.lastname: Axelrod
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Riggins
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Lu
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
authors.forename: Bassem R
authors.initials: BR
authors.lastname: Haddad
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC.
authors.forename: Bhaskar V
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
authors.forename: William T
authors.initials: WT
authors.lastname: Baumann
authors.affiliation: Department of Physiology and Biophysics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. clarker@georgetown.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008962:Models, Theoretical; D015398:Signal Transduction / Q000502:physiology*; D044764:Ubiquitin-Activating Enzymes / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D008565:Membrane Proteins; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes