Cancer-specific PERK signaling drives invasion and metastasis through CREB3L1

Yu-Xiong Feng, Dexter X. Jin, Ethan S. Sokol, Ferenc Reinhardt, Daniel H. Miller and Piyush B. Gupta ()
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Yu-Xiong Feng: Whitehead Institute for Biomedical Research
Dexter X. Jin: Whitehead Institute for Biomedical Research
Ethan S. Sokol: Whitehead Institute for Biomedical Research
Ferenc Reinhardt: Whitehead Institute for Biomedical Research
Daniel H. Miller: Whitehead Institute for Biomedical Research
Piyush B. Gupta: Whitehead Institute for Biomedical Research

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01052-y

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