title: FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7.
abstract: Amplification of chromosome 20q is frequently found in various types of human cancers, including breast cancer. The list of candidate oncogenes in 20q has expanded over the past decade. Here, we investigate whether FAM83D (family with sequence similarity 83, member D) on chromosome 20q plays any role in breast cancer development. The expression level of FAM83D is significantly elevated in breast cancer cell lines and primary human breast cancers. High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients. We show that ectopic expression of FAM83D in human mammary epithelial cells promotes cell proliferation, migration and invasion along with epithelial-mesenchymal transition (EMT). Ablation of FAM83D in breast cancer cells induces apoptosis and consequently inhibits cell proliferation and colony formation. Mechanistic studies reveal that overexpression of FAM83D downregulates FBXW7 expression levels through a physical interaction, which results in elevated protein levels of oncogenic substrates downstream to FBXW7, such as mTOR, whose inhibition by rapamycin can suppress FAM83D-induced cell migration and invasion. The results demonstrate that FAM83D has prognostic value for breast cancer patients and is a novel oncogene in breast cancer development that at least in part acts through mTOR hyper-activation by inhibiting FBXW7.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, USA.
authors.forename: Zeran
authors.initials: Z
authors.lastname: Wang
authors.forename: Yueyong
authors.initials: Y
authors.lastname: Liu
authors.forename: Pengju
authors.initials: P
authors.lastname: Zhang
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
authors.forename: Weijing
authors.initials: W
authors.lastname: Wang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Curr
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D016147:Genes, Tumor Suppressor; D006801:Humans; D008869:Microtubule-Associated Proteins; D011379:Prognosis; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C530359:FAM83D protein, human; C513273:FBXW7 protein, human; D008869:Microtubule-Associated Proteins; D044767:Ubiquitin-Protein Ligases