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- Title
Death-associated protein kinase 1 promotes growth of p53-mutant cancers.
- Authors
Jing Zhao; Dekuang Zhao; Poage, Graham M.; Mazumdar, Abhijit; Yun Zhang; Hill, Jamal L.; Hartman, Zachary C.; Savage, Michelle I.; Mills, Gordon B.; Brown, Powel H.
- Abstract
Estrogen receptor-negative (ER-negative) breast cancers are extremely aggressive and associated with poor prognosis. In particular, effective treatment strategies are limited for patients diagnosed with triple receptor-negative breast cancer (TNBC), which also carries the worst prognosis of all forms of breast cancer; therefore, extensive studies have focused on the identification of molecularly targeted therapies for this tumor subtype. Here, we sought to identify molecular targets that are capable of suppressing tumorigenesis in TNBCs. Specifically, we found that death-associated protein kinase 1 (DAPK1) is essential for growth of p53-mutant cancers, which account for over 80% of TNBCs. Depletion or inhibition of DAPK1 suppressed growth of p53-mutant but not p53-WT breast cancer cells. Moreover, 0APK1 inhibition limited growth of other p53-mutant cancers, including pancreatic and ovarian cancers. DAPK1 mediated the disruption of the TSC1/TSC2 complex, resulting in activation of the mTO R pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mT0R/S6K pathway; evaluation of multiple breast cancer patient data sets revealed that high DAPK1 expression associates with worse outcomes in individuals with p53-mutant cancers. Together, our data support targeting DAPK1 as a potential therapeutic strategy for p53-mutant cancers. Conflict of interest: Powel H. Brown is on the Scientific Advisory Board of Susan G. Komen for the Cure.
- Subjects
BREAST cancer research; CARCINOGENESIS; PROTEIN kinases; P53 protein; MTOR protein; CANCER cell growth; CELLULAR signal transduction
- Publication
Journal of Clinical Investigation, 2015, Vol 125, Issue 7, p2707
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI70805