Death-associated protein kinase 1 promotes growth of p53-mutant cancers
Jing Zhao, … , Gordon B. Mills, Powel H. Brown
Jing Zhao, … , Gordon B. Mills, Powel H. Brown
Published July 1, 2015; First published June 15, 2015
Citation Information: J Clin Invest. 2015;125(7):2707-2720. https://doi.org/10.1172/JCI70805.
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Research Article Oncology

Death-associated protein kinase 1 promotes growth of p53-mutant cancers

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, DAPK1 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 mTOR pathway. Our studies demonstrated that high DAPK1 expression causes increased cancer cell growth and enhanced signaling through the mTOR/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.

Authors

Jing Zhao, Dekuang Zhao, Graham M. Poage, Abhijit Mazumdar, Yun Zhang, Jamal L. Hill, Zachary C. Hartman, Michelle I. Savage, Gordon B. Mills, Powel H. Brown

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Figure 1

DAPK1 is differentially expressed in ER-negative and ER-positive breast cancers.

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DAPK1 is differentially expressed in ER-negative and ER-positive breast ...
mRNA and protein expression of DAPK1 in ER-positive and ER-negative breast cell lines and tumors. Fifteen human breast cell lines and 2 data sets were used to analyze the expression of DAPK1 in breast tumors. (A) mRNA expression of DAPK1 in 15 human breast cell lines. Each cell line was done in triplicate, and 2-tailed Student’s t test was used for statistical analysis. (B) Protein expression of DAPK1 in 15 human breast cell lines. The quantification of DAPK1 expression levels in noninvasive, ER-positive, and ER-negative cell lines is shown in the right panel, with results reported as average ± SEM. Two-tailed Student’s t test was used for statistical analysis. (C) mRNA expression of DAPK1 in ER-positive compared with ER-negative breast tumors in TCGA data set (368 samples) (4). (D) mRNA expression of DAPK1 in ER-positive compared with ER-negative in the Curtis data set (1944 samples) (20). See also Supplemental Figure 1. DAPK1 expression data were grouped according to clinical receptor status annotations, and DAPK1 expression was compared using box-and-whisker plots and presented on a log2 scale. Two-tailed Student’s t test was used for statistical analysis. (E) Immunohistochemical detection of DAPK1 and p53 in human patient tissue microarray tumor cores and a comparison of the proportion of patients with or without p53 staining associated with DAPK1 levels (right panel). Original magnification, ×40. Comparison of immunohistochemical staining was evaluated using Fisher’s exact test.