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

Wang Z, Liu Y, Zhang P, Zhang W, Wang W, Curr K, Wei G, Mao JH - Oncotarget (2013)

Bottom Line: The list of candidate oncogenes in 20q has expanded over the past decade.High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients.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.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, USA.

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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Elevated expression of FAM83D is associated with poor disease-free survival of breast cancer patients in four different cohorts (A) GSE1456, (B) GSE3494, (C) GSE6532, and (D) GSE20685FAM83D expression is measured as log2 (probe intensities). The p-values were obtained from a long-rank test.
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Figure 2: Elevated expression of FAM83D is associated with poor disease-free survival of breast cancer patients in four different cohorts (A) GSE1456, (B) GSE3494, (C) GSE6532, and (D) GSE20685FAM83D expression is measured as log2 (probe intensities). The p-values were obtained from a long-rank test.

Mentions: To investigate the clinical impact of elevated FAM83D expression in human breast cancer, we assessed the association between FAM83D mRNA levels and clinical outcome in four independent breast cancer cohorts [36-39] with clinical information (GEO database). To determine the prognostic impact of FAM83D expression in breast cancer, we categorized breast cancer patients into three groups based on FAM83D mRNA expression levels (low=bottom tertile, intermediate=middle tertile, and high=top tertile). Patients with tumors displaying high FAM83D expression levels had significantly shorter disease-free survival (DFS) compared to those with low FAM83D (p=0.0011, 0.0063, 1.93E-5 and 0.0021 in dataset GSE1456, GSE3494, GSE6532 and GSE20685, respectively) (Fig. 2). Moreover, in all four datasets, DFS curves for patients with intermediate levels of FAM83D was between those with high and low levels (Fig. 2), suggesting a dose-dependent effect of FAM83D expression on DFS.


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

Wang Z, Liu Y, Zhang P, Zhang W, Wang W, Curr K, Wei G, Mao JH - Oncotarget (2013)

Elevated expression of FAM83D is associated with poor disease-free survival of breast cancer patients in four different cohorts (A) GSE1456, (B) GSE3494, (C) GSE6532, and (D) GSE20685FAM83D expression is measured as log2 (probe intensities). The p-values were obtained from a long-rank test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926842&req=5

Figure 2: Elevated expression of FAM83D is associated with poor disease-free survival of breast cancer patients in four different cohorts (A) GSE1456, (B) GSE3494, (C) GSE6532, and (D) GSE20685FAM83D expression is measured as log2 (probe intensities). The p-values were obtained from a long-rank test.
Mentions: To investigate the clinical impact of elevated FAM83D expression in human breast cancer, we assessed the association between FAM83D mRNA levels and clinical outcome in four independent breast cancer cohorts [36-39] with clinical information (GEO database). To determine the prognostic impact of FAM83D expression in breast cancer, we categorized breast cancer patients into three groups based on FAM83D mRNA expression levels (low=bottom tertile, intermediate=middle tertile, and high=top tertile). Patients with tumors displaying high FAM83D expression levels had significantly shorter disease-free survival (DFS) compared to those with low FAM83D (p=0.0011, 0.0063, 1.93E-5 and 0.0021 in dataset GSE1456, GSE3494, GSE6532 and GSE20685, respectively) (Fig. 2). Moreover, in all four datasets, DFS curves for patients with intermediate levels of FAM83D was between those with high and low levels (Fig. 2), suggesting a dose-dependent effect of FAM83D expression on DFS.

Bottom Line: The list of candidate oncogenes in 20q has expanded over the past decade.High expression levels of FAM83D are significantly associated with poor clinical outcome and distant metastasis in breast cancer patients.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.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, USA.

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.

Show MeSH
Related in: MedlinePlus