title: BikDDA, a mutant of Bik with longer half-life expression protein, can be a novel therapeutic gene for triple-negative breast cancer.
abstract: Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro.
authors.affiliation: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China; Department of Cancer Prevention Center, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
authors.forename: Minqing
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China; Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xie
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins; D058990:Molecular Targeted Therapy; D015999:Multivariate Analysis; D050505:Mutant Proteins / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000601:surgery / Q000628:therapy*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D014408:Biomarkers, Tumor; C579095:MCL1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051020:bcl-X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D005472:Fluorouracil