MAPK4 Promotes Triple Negative Breast Cancer Growth and Reduces Tumor Sensitivity to PI3K Blockade

Authors

Wei Wang
Dong Han
Qinbo Cai
Tao Shen
Bingning Dong
Michael T Lewis
Runsheng Wang
Yanling Meng
Wolong Zhou
Ping Yi
Chad J Creighton
David D Moore
Feng Yang

Publication Date

1-11-2022

Journal

Nature Communications

DOI

10.1038/s41467-021-27921-1

PMID

35017531

PMCID

PMC8752662

PubMedCentral® Posted Date

1-11-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Animals, Breast Neoplasms, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, SCID, Mitogen-Activated Protein Kinases, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt, RNA Helicases, Signal Transduction, TOR Serine-Threonine Kinases, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays

Abstract

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity to PI3K inhibition. Accordingly, repressing MAPK4 greatly sensitizes TNBC cells and xenografts to PI3K blockade. Altogether, we conclude that high MAPK4 expression defines a large subset or subtype of TNBC responsive to MAPK4 blockage. Targeting MAPK4 in this subset/subtype of TNBC both represses growth and sensitizes tumors to PI3K blockade.

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