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Lani · 06-08-2015, 09:46 AM

Sci Signal. 2015 May 26;8(378):ra52. doi: 10.1126/scisignal.aaa6922.
HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive
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Singh N1, Joshi R1, Komurov K2.

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.
Copyright © 2015, American Association for the Advancement of Science.
PMID: 26012635 [PubMed - in process]

06-08-2015, 09:46 AM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	another door to shut to keep the "puppy" from escaping to the yard to chase squirrels Sci Signal. 2015 May 26;8(378):ra52. doi: 10.1126/scisignal.aaa6922. HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive . Singh N1, Joshi R1, Komurov K2. 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. Copyright © 2015, American Association for the Advancement of Science. PMID: 26012635 [PubMed - in process]