title: IκB kinases increase Myc protein stability and enhance progression of breast cancer cells.
abstract: BACKGROUND
  Both IκB kinase (IKK) complex and oncgenic protein Myc play important roles in cancer progression, including cancer cell invasiveness and metastasis. The levels of Myc is regulated by the phosphorylation of Myc at Thr58 and Ser62.
  
  
  RESULTS
  In this study, we show that the expression of Myc is associated with IKKα and IKKβ in breast cancers and that Myc is an IKKs substrate. Suppression of IKK activity by either chemical inhibitor or transfection of kinase-dead mutants decreases the phosphorylation of Myc at Ser62 and enhances the degradation of Myc. Consequently, these treatments decrease the tumorigenic and invasive ability of breast cancer cells. Furthermore, doxorubicin, a frequently used anticancer drug in breast cancer, activates IKKs and Myc, thereby increasing invasiveness and tumorigenesis of breast carcinoma MCF7 cells. Inhibition of IKKs prevents these doxorubicin-induced effects.
  
  
  CONCLUSIONS
  Our study indicates that IKKs tightly regulate Myc expression through prolonging protein stability, and suggests that IKKs are potentially therapeutic targets and that suppression of IKKs may be used following chemotherapy to reduce the risk of treatment-induced tumor progression.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, No, 7, Chung-Shan South Road, Taipei, 100, Taiwan.
authors.forename: Pei-Yen
authors.initials: PY
authors.lastname: Yeh
authors.forename: Yen-Shen
authors.initials: YS
authors.lastname: Lu
authors.forename: Da-Liang
authors.initials: DL
authors.lastname: Ou
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D016328:NF-kappa B; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D013450:Sulfones; D004317:Doxorubicin; D051550:I-kappa B Kinase