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Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel
Wang,Haitao1,2; Guo,Sen1,2; Kim,Seung Jin3; Shao,Fangyuan1,2; Kei Ho,Joshua Wing4; Wong,Kuan Un1,2; Miao,Zhengqiang1,2; Hao,Dapeng1,2; Zhao,Ming1,2; Xu,Jun1,2; Zeng,Jianming1,2; Wong,Koon Ho1,5; Di,Lijun1,2; Wong,Ada Hang Heng1,2; Xu,Xiaoling1,2; Deng,Chu Xia1,2
2021
Source PublicationTheranostics
ISSN1838-7640
Volume11Issue:5Pages:2442-2459
Abstract

Cancer growth is usually accompanied by metastasis which kills most cancer patients. Here we aim to study the effect of cisplatin at different doses on breast cancer growth and metastasis. Methods: We used cisplatin to treat breast cancer cells, then detected the migration of cells and the changes of epithelial-mesenchymal transition (EMT) markers by migration assay, Western blot, and immunofluorescent staining. Next, we analyzed the changes of RNA expression of genes by RNA-seq and confirmed the binding of activating transcription factor 3 (ATF3) to cytoskeleton related genes by ChIP-seq. Thereafter, we combined cisplatin and paclitaxel in a neoadjuvant setting to treat xenograft mouse models. Furthermore, we analyzed the association of disease prognosis with cytoskeletal genes and ATF3 by clinical data analysis. Results: When administered at a higher dose (6 mg/kg), cisplatin inhibits both cancer growth and metastasis, yet with strong side effects, whereas a lower dose (2 mg/kg) cisplatin blocks cancer metastasis without obvious killing effects. Cisplatin inhibits cancer metastasis through blocking early steps of EMT. It antagonizes transforming growth factor beta (TGFβ) signaling through suppressing transcription of many genes involved in cytoskeleton reorganization and filopodia formation which occur early in EMT and are responsible for cancer metastasis. Mechanistically, TGFβ and fibronectin-1 (FN1) constitute a positive reciprocal regulation loop that is critical for activating TGFβ/SMAD3 signaling, which is repressed by cisplatin induced expression of ATF3. Furthermore, neoadjuvant administration of cisplatin at 2 mg/kg in conjunction with paclitaxel inhibits cancer growth and blocks metastasis without causing obvious side effects by inhibiting colonization of cancer cells in the target organs. Conclusion: Thus, cisplatin prevents breast cancer metastasis through blocking early EMT, and the combination of cisplatin and paclitaxel represents a promising therapy for killing breast cancer and blocking tumor metastasis.

KeywordCisplatin Metastasis Neoadjuvant Therapy Paclitaxel Tgfβ
DOI10.7150/thno.46460
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaResearch & Experimental Medicine
WOS SubjectMedicine, Research & Experimental
WOS IDWOS:000600556000030
Scopus ID2-s2.0-85098646642
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorDeng,Chu Xia
Affiliation1.Cancer Center,Faculty of Health Sciences,University of Macau,Macao
2.Center for Precision Medicine Research and Training,University of Macau,Macao
3.Genetics of Development and Disease Branch,National Institute of Diabetes,Digestive and Kidney Diseases,National Institutes of Health,Bethesda,10/9N105,20892,United States
4.School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,University of Hong Kong,Hong Kong,Hong Kong
5.Institute of Translational Medicine,Faculty of Health Sciences,University of Macau,Macao
First Author AffilicationCancer Centre;  University of Macau
Corresponding Author AffilicationCancer Centre;  University of Macau
Recommended Citation
GB/T 7714
Wang,Haitao,Guo,Sen,Kim,Seung Jin,et al. Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel[J]. Theranostics,2021,11(5):2442-2459.
APA Wang,Haitao,Guo,Sen,Kim,Seung Jin,Shao,Fangyuan,Kei Ho,Joshua Wing,Wong,Kuan Un,Miao,Zhengqiang,Hao,Dapeng,Zhao,Ming,Xu,Jun,Zeng,Jianming,Wong,Koon Ho,Di,Lijun,Wong,Ada Hang Heng,Xu,Xiaoling,&Deng,Chu Xia.(2021).Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel.Theranostics,11(5),2442-2459.
MLA Wang,Haitao,et al."Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel".Theranostics 11.5(2021):2442-2459.
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