title: HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive.
abstract: Targeting non-oncogenic vulnerabilities may provide additional therapeutic approaches in tumors that are resistant to oncogene-targeted therapy. Using a computational pathway-based approach, we interrogated clinical breast cancer genomic data sets for candidate non-oncogenic vulnerabilities in breast cancers that have genomic amplification of ERBB2, which encodes human epidermal growth factor 2 (HER2). HER2-positive (HER2(+)) breast cancers showed increased expression of genes encoding proteins in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Genetic ablation or pharmacological inhibition of ERAD led to irrecoverable ER stress and selectively killed HER2(+) breast cancer cells. Cell death caused by ERAD inhibition partially depended on increased HER2-mTOR signaling, which imposed an increased proteotoxic burden on the ER. Cell death in response to ER stress required the IRE1α-JNK pathway, which was selectively suppressed in HER2(+) breast cancers by phosphatases that inactivate JNK. Accordingly, the cytotoxicity of inhibiting ERAD as well as JNK phosphatases was synergistic in HER2(+) but not in HER2-negative breast cancer cells. Therefore, our study suggests that reactivation of oncogene-induced stress by targeting stress-adaptive pathways may be a beneficial approach for therapy-resistant breast cancers.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Navneet
authors.initials: N
authors.lastname: Singh
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Rashika
authors.initials: R
authors.lastname: Joshi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. kakajan.komurov@cchmc.org.
authors.forename: Kakajan
authors.initials: K
authors.lastname: Komurov
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004722:Endoribonucleases; D048670:MAP Kinase Kinase 4; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C528229:ERN1 protein, human