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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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mTOR inhibition by rapamycin alleviates the enhanced migration and invasion caused by ectopic overexpression of FAM83D(A) Inhibition of mTOR by rapamycin significantly suppresses cell motility induced by FAM83D ectopic overexpression in scratch-healing assay. The representative photographs are shown in left panel. Quantification of the data was presented as relative migration area in each cell line (right panel). (B and C) Enhanced cell migration and invasion caused by FAM83D ectopic overexpression were rescued by treatment of Rapamycin. Uncoated (B) or Matrigel-coated (C) transwell assays on MCF10A control cells and MCF10A-FAM83D cells treated with DMSO control and rapamycin. In a-c, data are presented as means ± Standard deviation from three independent experiments each performed in triplicates. ** indicates p<0.01, which were obtained from t-test. (D) Schematic illustration of the proposed oncogenic function of FAM83D in breast cancer development through inhibition of the FBXW7 tumor suppressor by physical interaction.
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Figure 7: mTOR inhibition by rapamycin alleviates the enhanced migration and invasion caused by ectopic overexpression of FAM83D(A) Inhibition of mTOR by rapamycin significantly suppresses cell motility induced by FAM83D ectopic overexpression in scratch-healing assay. The representative photographs are shown in left panel. Quantification of the data was presented as relative migration area in each cell line (right panel). (B and C) Enhanced cell migration and invasion caused by FAM83D ectopic overexpression were rescued by treatment of Rapamycin. Uncoated (B) or Matrigel-coated (C) transwell assays on MCF10A control cells and MCF10A-FAM83D cells treated with DMSO control and rapamycin. In a-c, data are presented as means ± Standard deviation from three independent experiments each performed in triplicates. ** indicates p<0.01, which were obtained from t-test. (D) Schematic illustration of the proposed oncogenic function of FAM83D in breast cancer development through inhibition of the FBXW7 tumor suppressor by physical interaction.

Mentions: Since FAM83D directly regulates FBXW7 to control cell growth and motility, we tested whether inhibition of downstream substrates of FBXW7 can suppress oncogenic phenotypes induced by FAM83D overexpression. We focused on mTOR, since our previous study showed that mTOR inhibition by rapamycin suppresses EMT, invasion and stemness driven by loss of FBXW7 in colon cancer cells [40]. As shown in Fig. 7A, rapamycin treatment significantly decreased the closure rate of MCF10A-FAM83D cells in the scratch healing assay. Consistent with this result, rapamycin also significantly decreased migration (Fig. 7B) and invasion (Fig. 7C) of MCF10A-FAM83D cells in the Boyden chamber assay. These results indicate that FAM83D executes oncogenic functions via regulation of FBXW7, which can be attenuated by inhibition of mTOR signaling, an FBXW7-downstream target.


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)

mTOR inhibition by rapamycin alleviates the enhanced migration and invasion caused by ectopic overexpression of FAM83D(A) Inhibition of mTOR by rapamycin significantly suppresses cell motility induced by FAM83D ectopic overexpression in scratch-healing assay. The representative photographs are shown in left panel. Quantification of the data was presented as relative migration area in each cell line (right panel). (B and C) Enhanced cell migration and invasion caused by FAM83D ectopic overexpression were rescued by treatment of Rapamycin. Uncoated (B) or Matrigel-coated (C) transwell assays on MCF10A control cells and MCF10A-FAM83D cells treated with DMSO control and rapamycin. In a-c, data are presented as means ± Standard deviation from three independent experiments each performed in triplicates. ** indicates p<0.01, which were obtained from t-test. (D) Schematic illustration of the proposed oncogenic function of FAM83D in breast cancer development through inhibition of the FBXW7 tumor suppressor by physical interaction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 7: mTOR inhibition by rapamycin alleviates the enhanced migration and invasion caused by ectopic overexpression of FAM83D(A) Inhibition of mTOR by rapamycin significantly suppresses cell motility induced by FAM83D ectopic overexpression in scratch-healing assay. The representative photographs are shown in left panel. Quantification of the data was presented as relative migration area in each cell line (right panel). (B and C) Enhanced cell migration and invasion caused by FAM83D ectopic overexpression were rescued by treatment of Rapamycin. Uncoated (B) or Matrigel-coated (C) transwell assays on MCF10A control cells and MCF10A-FAM83D cells treated with DMSO control and rapamycin. In a-c, data are presented as means ± Standard deviation from three independent experiments each performed in triplicates. ** indicates p<0.01, which were obtained from t-test. (D) Schematic illustration of the proposed oncogenic function of FAM83D in breast cancer development through inhibition of the FBXW7 tumor suppressor by physical interaction.
Mentions: Since FAM83D directly regulates FBXW7 to control cell growth and motility, we tested whether inhibition of downstream substrates of FBXW7 can suppress oncogenic phenotypes induced by FAM83D overexpression. We focused on mTOR, since our previous study showed that mTOR inhibition by rapamycin suppresses EMT, invasion and stemness driven by loss of FBXW7 in colon cancer cells [40]. As shown in Fig. 7A, rapamycin treatment significantly decreased the closure rate of MCF10A-FAM83D cells in the scratch healing assay. Consistent with this result, rapamycin also significantly decreased migration (Fig. 7B) and invasion (Fig. 7C) of MCF10A-FAM83D cells in the Boyden chamber assay. These results indicate that FAM83D executes oncogenic functions via regulation of FBXW7, which can be attenuated by inhibition of mTOR signaling, an FBXW7-downstream target.

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