Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1
Authors: Jian Shi
Gang Wang
Binhua P Zhou
Xin Wang
Tiebang Kang
Renxian Cao
Meifang Zhang
Rou Jiang
Jingying Cao
Ruhua Zhang
Yuanzhong Wu
Tao Dai
Journal: Theranostics (2018)
Discipline: CLINICAL MEDICINE
Keywords: EMT; ROR1; Twist; basal-like breast cancer (BLBC); tumor metastasis.
Affiliations: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China., Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA., Department of Medicine Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha, 410013, P. R. China., Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University, Hunan Cancer Hospital, Changsha, 410013, P. R. China., Institute of Clinical Medicine, the First Affiliated Hospital of University of South China, Hengyang, P. R. China., Department of Pathology, School of Basic Medical Science; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou 510515, China.

Abstract:  Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive. Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients. Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients. Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells. 

Retracted: No

PubPeer comments:
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 The lack of observation of the inhibitory ternary complex in Fig 5C and 5D is suspect (the complex can be seen in Fig 5B as the upper TS band). 5-FU elicits cellular toxicity through 3 pathways: RNA incorporation, DNA incorporation, and TS inhibition. The authors show that thymidine can reverse 5-FU polarization on Th1 and Th17 cells in vitro, suggesting TS plays a role in the observed effect. However, mice have high plasma thymidine levels (~1 uM; Am J Clin Nutr 2015;101:860). Thus, any effect in their animal model cannot be attributed to TS inhibition. , 
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