title: STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious.
abstract: Autophagy is a protein and organelle degradation pathway that is involved in diverse diseases, including cancer. Recent evidence suggests that autophagy is a cell survival mechanism in tumor cells and that its inhibition, especially in combination with other therapy, could be beneficial but it remains unclear if all cancer cells behave the same way when autophagy is inhibited. We inhibited autophagy in a panel of breast cancer cell lines and found that some of them are dependent on autophagy for survival even in nutrient rich conditions without any additional stress, whereas others need autophagy only when stressed. Survival under unstressed conditions is due to cell type-specific autophagy regulation of STAT3 activity and this phenotype is enriched in triple-negative cell lines. This autophagy-dependency affects response to therapy because autophagy inhibition reduced tumor growth in vivo in autophagy-dependent but not in autophagy-independent breast tumors, whereas combination treatment with autophagy inhibitors and other agent was preferentially synergistic in autophagy-dependent cells. These results imply that autophagy-dependence represents a tumor cell-specific characteristic where autophagy inhibition will be more effective. Moreover, our results suggest that autophagy inhibition might be a potential therapeutic strategy for triple-negative breast cancers, which currently lack an effective targeted treatment.
authors.affiliation: Authors' Affiliations: Departments of Pharmacology, and Pediatrics, University of Colorado School of Medicine, Aurora; and Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado.
authors.forename: Paola
authors.initials: P
authors.lastname: Maycotte
authors.forename: Christy M
authors.initials: CM
authors.lastname: Gearheart
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barnard
authors.forename: Suraj
authors.initials: S
authors.lastname: Aryal
authors.forename: Jean M
authors.initials: JM
authors.lastname: Mulcahy Levy
authors.forename: Susan P
authors.initials: SP
authors.lastname: Fosmire
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morgan
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Porter
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004317:Doxorubicin; D002738:Chloroquine; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes