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CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKK?.


ABSTRACT: Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, cell migration and invasion were significantly reduced, as was the establishment of metastasis following intracardiac administration in athymic nude mice. To explore the mechanism behind these effects, gene expression following CITED2 knockdown in MDA-MB-231 cells by cDNA microarray was performed. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-?B regulator IKK? was significantly reduced, along with several NF-?B targets with known roles in metastasis (OPN, MMP9, uPA, SPARC, IL11, and IL1?). Furthermore, ChIP assay revealed recruitment of CITED2 to the promoter of IKK?, indicating a direct role in regulating its expression. Consistent with reduced IKK? expression, CITED2 knockdown inhibited both canonical and noncanonical NF-?B signaling. Finally, restoration of IKK? expression following CITED2 knockdown in MDA-MB-231 and MDA-MB-468 cells rescued their invasive ability. Collectively, these data demonstrate that CITED2 modulates metastatic ability in human breast cancer cells, at least in part, through the regulation of IKK?.The current study highlights the role of CITED2 in facilitating breast cancer metastasis, partly via regulation of IKK?. Mol Cancer Res; 14(8); 730-9. ©2016 AACR.

SUBMITTER: Jayaraman S 

PROVIDER: S-EPMC4987170 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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CITED2 Modulates Breast Cancer Metastatic Ability through Effects on IKKα.

Jayaraman Swaathi S   Doucet Michele M   Lau Wen Min WM   Kominsky Scott L SL  

Molecular cancer research : MCR 20160523 8


<h4>Unlabelled</h4>Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, C  ...[more]

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