title: FOXP3 suppresses breast cancer metastasis through downregulation of CD44.
abstract: Forkhead box protein 3 (FOXP3) plays an important role in breast cancer as an X-linked tumor suppressor gene. However, the biological functions and significance of FOXP3 in breast cancer metastasis remain unclear. Here, we find that, clinically, nuclear FOXP3 expression is inversely correlated with breast cancer metastasis. Moreover, we demonstrate that FOXP3 significantly inhibits adhesion, invasion and metastasis of breast cancer cells in vivo and in vitro. In addition, the adhesion molecule CD44 is found to be suppressed by FOXP3 through transcriptome sequence analysis (RNA-seq). A luciferase reporter assay, chromatin immunoprecipitation and electrophoretic mobility shift assay identify CD44 as a direct target of FOXP3. The expression of CD44 is downregulated by FOXP3 in breast cancer cells. Importantly, anti-CD44 antibody reverses the FOXP3 siRNA-induced effects on the breast cancer cells in vitro and FOXP3 expression level in the nucleus of breast cancer cells is inversely correlated with CD44 expression level in clinic breast cancer tissues. Taken together, the results from the present study suggest that FOXP3 is a suppressor of breast cancer metastasis. FOXP3 directly binds to the promoter of CD44 and inhibits its protein expression, thereby suppressing adhesion and invasion of human breast cancer cells. This finding highlights the therapeutic potential of FOXP3-CD44 signaling to inhibit breast cancer metastasis.
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Cun
authors: C
authors: Zhang
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Yujin
authors: Y
authors: Xu
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Qiang
authors: Q
authors: Hao
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Shuning
authors: S
authors: Wang
authors: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors: Hong
authors: H
authors: Li
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Jialin
authors: J
authors: Li
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Yuan
authors: Y
authors: Gao
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Meng
authors: M
authors: Li
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Weina
authors: W
authors: Li
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Xiaochang
authors: X
authors: Xue
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Shouzhen
authors: S
authors: Wu
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Yingqi
authors: Y
authors: Zhang
authors: State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, the Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
authors: Wei
authors: W
authors: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C497483:CD44 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018960:Hyaluronan Receptors; D025521:Tumor Suppressor Proteins