Oncotarget

Research Papers:

FAM83D promotes cell proliferation and motility by downregulating tumor suppressor gene FBXW7

Zeran Wang, Yueyong Liu, Pengju Zhang, Weiguo Zhang, Weijing Wang, Kenneth Curr, Guangwei Wei and Jian-Hua Mao _

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Oncotarget. 2013; 4:2476-2486. https://doi.org/10.18632/oncotarget.1581

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Abstract

Zeran Wang1,2,*, Yueyong Liu1,*, Pengju Zhang3,1,*, Weiguo Zhang1, Weijing Wang1,4, Kenneth Curr2, Guangwei Wei5,1, Jian-Hua Mao1

1 Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, USA

2 Department of Biology, California State University East Bay, Hayward, California, USA.

3 Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China

4 Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA

5 Department of Anatomy, Shandong University School of Medicine, Building 1, Jinan, Shandong, P.R. China

* These authors contributed equally to this paper.

Correspondence:

Jian-Hua Mao, email:

Keywords: FAM83D, FBXW7, breast cancer, epithelial-mesenchymal transition, invasion

Received: November 5, 2013 Accepted: November 23, 2013 Published: November 25, 2013

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.


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