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FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-?B signaling.

ABSTRACT: Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-?B (NF-?B) in BLBC cells by increasing p65/RelA protein stability. High NF-?B activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-?B for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-?B. These results suggest that BLBC cells may rely on FOXC1-driven NF-?B signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.

SUBMITTER: Wang J

PROVIDER: S-EPMC3961006 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling.

Wang J J Ray P S PS Sim M-S MS Zhou X Z XZ Lu K P KP Lee A V AV Lin X X Bagaria S P SP Giuliano A E AE Cui X X

Oncogene 20120116 45

Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BL ...[more]

PMID: 22249250

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Project description:Objective:Breast cancer has become the most common malignancy among women worldwide; therefore, novel diagnostic and prognostic markers and therapeutic targets are urgently required. NF-?B signaling plays a pivotal role in enhancing breast cancer malignant phenotypes, especially cancer invasion and metastasis, which is the main cause of death in cancer patients. TNIP2, an important inhibitor of the NF-?B pathway, is known to involve a negative feedback loop of the NF-?B signaling cascade and to regulate tumor aggressiveness in various cancer types. However, the mRNA level of TNIP2 is barely altered in breast cancer; thus, the mechanism that regulates TNIP2 in breast cancer still needs to be elucidated. Methods:We analyzed the expression and prognosis of miR-423 in a TCGA BRCA miRNA cohort and in clinical specimens. We detected the invasive capacity through a Matrigel-coated Transwell penetration assay, a three-dimensional (3D) spheroid invasion assay and a wound healing assay. Then, we applied luciferase assays, real-time PCR assays and Western blotting to further study the mechanism. Results:In this study, analysis of the TCGA BRCA miRNA cohort and clinical specimens demonstrated that miR-423 was upregulated in human breast cancers and was positively correlated with clinical stage, poor overall survival and metastasis classification. Moreover, the invasiveness of breast cancer cells was enhanced by ectopic expression of miR-423 and inhibited by miR-423 downregulation. Mechanistically, upregulation of miR-423 led to activation of the NF-?B signaling pathway and elevated expression of snail and twist, while repression of miR-423 inhibited this pathway. Furthermore, the results indicated that TNIP2 is a target gene of miR-423, and suppression of TNIP2 resulted in increased invasiveness in miR-423-silenced cells. Conclusion:Our results suggest that miR-423 is a crucial factor that enhances breast cancer cell invasion through the NF-?B signaling pathway and shed light on miR-423 as a promising prognostic and therapeutic marker for metastatic breast cancer.

Dataset Information

FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-?B signaling.

Publications

FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling.

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