FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2

S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that f...

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Veröffentlicht in:The Journal of clinical investigation 2007-12, Vol.117 (12), p.3765-3773
Hauptverfasser: Zuo, Tao, Liu, Runhua, Zhang, Huiming, Chang, Xing, Liu, Yan, Wang, Lizhong, Zheng, Pan, Liu, Yang
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container_issue 12
container_start_page 3765
container_title The Journal of clinical investigation
container_volume 117
creator Zuo, Tao
Liu, Runhua
Zhang, Huiming
Chang, Xing
Liu, Yan
Wang, Lizhong
Zheng, Pan
Liu, Yang
description S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that forkhead box P3 (FOXP3) is an X-linked breast cancer suppressor and an important repressor of the oncogene ERBB2/HER2. Since FOXP3 suppresses tumor growth regardless of whether the tumors overexpress ERBB2/HER2, additional FOXP3 targets may be involved in its tumor suppressor activity. Here, we show that mammary carcinomas from mice heterozygous for a Foxp3 mutation exhibited increased Skp2 expression. Ectopic expression of FOXP3 in mouse mammary cancer cells repressed SKP2 expression with a corresponding increase in p27 and polyploidy. Conversely, siRNA silencing of the FOXP3 gene in human mammary epithelial cells increased SKP2 expression. We also show that Foxp3 directly interacted with and repressed the Skp2 promoter. Moreover, the analysis of over 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. Finally, we demonstrated that downregulation of SKP2 was critical for FOXP3-mediated growth inhibition in breast cancer cells that do not overexpress ERBB2/HER2. Our data provide genetic, biochemical, and functional evidence that FOXP3 is a novel transcriptional repressor for the oncogene SKP2.
doi_str_mv 10.1172/jci32538
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subjects Animals
Biomedical research
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Cullin Proteins - genetics
Cullin Proteins - metabolism
DNA binding proteins
Female
Forkhead Transcription Factors - antagonists & inhibitors
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - genetics
Gene Silencing
Genes, X-Linked
Genetic aspects
Health aspects
Heterozygote
Humans
Identification and classification
Mice
Mice, Inbred BALB C
Mice, Mutant Strains
Oncogene Proteins - antagonists & inhibitors
Oncogene Proteins - genetics
Oncogene Proteins - metabolism
Ploidies
Receptor, ErbB-2 - genetics
Receptor, ErbB-2 - metabolism
Repressor Proteins - antagonists & inhibitors
Repressor Proteins - genetics
Repressor Proteins - metabolism
Risk factors
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
S-Phase Kinase-Associated Proteins - antagonists & inhibitors
S-Phase Kinase-Associated Proteins - genetics
S-Phase Kinase-Associated Proteins - metabolism
Tumor suppressor genes
Tumor Suppressor Proteins - antagonists & inhibitors
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
title FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2
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