Abstract
PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy. Unfortunately, chemical inhibitors of PERK’s kinase activity cause on-target side effects that have precluded their further development. One strategy for resolving this difficulty would be to target downstream components of the pathway that specifically mediate PERK’s pro-invasive and metastatic functions. Here we identify the transcription factor CREB3L1 as an essential mediator of PERK’s pro-metastatic functions in breast cancer. CREB3L1 acts downstream of PERK, specifically in the mesenchymal subtype of triple-negative tumors, and its inhibition by genetic or pharmacological methods suppresses cancer cell invasion and metastasis. In patients with this tumor subtype, CREB3L1 expression is predictive of distant metastasis. These findings establish CREB3L1 as a key downstream mediator of PERK-driven metastasis and a druggable target for breast cancer therapy.
Highlights
PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy
Consistent with prior reports[13], we found that PERK is activated by phosphorylation in human breast cancers (Supplementary Fig. 1a)
To identify factors downstream of PERK upregulated in human breast cancers, we compared PERK pathway gene expression between a large cohort of breast cancers (n = 1093) and normal breast tissues (n = 112) (TCGA, breast cancer data set)
Summary
PERK signaling is required for cancer invasion and there is interest in targeting this pathway for therapy. Given its critical role in driving metastatic progression, PERK has been a focus of drug discovery programs for cancer, which have identified several small-molecule inhibitors of this kinase that reduce metastatic dissemination[13]. While these molecules reduce metastatic spread, they cause rapid onset of pancreatic atrophy, precluding their further consideration for clinical development[14]. We show that this is the case, and identify a key transcription factor (CREB3L1) downstream in the pathway, that functions to promote metastasis in cancer cells that have activated PERK. Our findings establish CREB3L1 as a promising target downstream of the PERK pathway for therapeutic blockade in cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
