title: Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression.
abstract: High expression of the oncoprotein Myc has been linked to poor outcome in human tumors. Although MYC gene amplification and translocations have been observed, this can explain Myc overexpression in only a subset of human tumors. Myc expression is in part controlled by its protein stability, which can be regulated by phosphorylation at threonine 58 (T58) and serine 62 (S62). We now report that Myc protein stability is increased in a number of breast cancer cell lines and this correlates with increased phosphorylation at S62 and decreased phosphorylation at T58. Moreover, we find this same shift in phosphorylation in primary breast cancers. The signaling cascade that controls phosphorylation at T58 and S62 is coordinated by the scaffold protein Axin1. We therefore examined Axin1 in breast cancer and report decreased AXIN1 expression and a shift in the ratio of expression of two naturally occurring AXIN1 splice variants. We demonstrate that this contributes to increased Myc protein stability, altered phosphorylation at S62 and T58, and increased oncogenic activity of Myc in breast cancer. Thus, our results reveal an important mode of Myc activation in human breast cancer and a mechanism contributing to Myc deregulation involving unique insight into inactivation of the Axin1 tumor suppressor in breast cancer.
authors.affiliation: Molecular and Medical Genetics Department, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Amy S
authors.initials: AS
authors.lastname: Farrell
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Daniel
authors.forename: Hugh
authors.initials: H
authors.lastname: Arnold
authors.forename: Charles
authors.initials: C
authors.lastname: Scanlan
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Laraway
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Janghorban
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
authors.forename: Dexi
authors.initials: D
authors.lastname: Chen
authors.forename: Megan
authors.initials: M
authors.lastname: Troxell
authors.forename: Rosalie
authors.initials: R
authors.lastname: Sears
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: C555451:AXIN1 protein, human; D060466:Axin Protein; D016271:Proto-Oncogene Proteins c-myc; D010768:Phosphoserine