TRIM29 Suppresses TWIST1 and Invasive Breast Cancer Behavior

TRIM29 (ATDC) exhibits a contextual function in cancer, but seems to exert a tumor-suppressor role in breast cancer. Here, we show that TRIM29 is often silenced in primary breast tumors and cultured tumor cells as a result of aberrant gene hypermethylation. RNAi-mediated silencing of TRIM29 in breas...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2014-09, Vol.74 (17), p.4875-4887
Hauptverfasser: LINGBAO AI, KIM, Wan-Ju, BROWN, Kevin D, ALPAY, Merve, MING TANG, PARDO, Carolina E, HATAKEYAMA, Shigetsugu, STRATFORD MAY, W, KLADDE, Michael P, HELDERMON, Coy D, SIEGEL, Erin M
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Sprache:eng
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Zusammenfassung:TRIM29 (ATDC) exhibits a contextual function in cancer, but seems to exert a tumor-suppressor role in breast cancer. Here, we show that TRIM29 is often silenced in primary breast tumors and cultured tumor cells as a result of aberrant gene hypermethylation. RNAi-mediated silencing of TRIM29 in breast tumor cells increased their motility, invasiveness, and proliferation in a manner associated with increased expression of mesenchymal markers (N-cadherin and vimentin), decreased expression of epithelial markers (E-cadherin and EpCAM), and increased expression and activity of the oncogenic transcription factor TWIST1, an important driver of the epithelial-mesenchymal transition (EMT). Functional investigations revealed an inverse relationship in the expression of TRIM29 and TWIST1, suggesting the existence of a negative regulatory feedback loop. In support of this relationship, we found that TWIST1 inhibited TRIM29 promoter activity through direct binding to a region containing a cluster of consensus E-box elements, arguing that TWIST1 transcriptionally represses TRIM29 expression. Analysis of a public breast cancer gene-expression database indicated that reduced TRIM29 expression was associated with reduced relapse-free survival, increased tumor size, grade, and metastatic characteristics. Taken together, our results suggest that TRIM29 acts as a tumor suppressor in breast cancer through its ability to inhibit TWIST1 and suppress EMT.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-13-3579