title: 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.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Dekuang
authors.initials: D
authors.lastname: Zhao
authors.forename: Graham M
authors.initials: GM
authors.lastname: Poage
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mazumdar
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jamal L
authors.initials: JL
authors.lastname: Hill
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Savage
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C546842:MTOR protein, human; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D058570:TOR Serine-Threonine Kinases