Vascular endothelial growth factor receptor-1 activation promotes migration and invasion of breast cancer cells through epithelial-mesenchymal transition
Authors: Min Meng
Xinhan Zhao
Shan Shao
Minna Luo
Qian Ning
Lei Hou
Caigang Liu
Xiaoxiao Zuo
Xiaojin Zhang
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: VEGFR-1; breast cancer; invasiveness; PlGF; EMT
Affiliations: Department of Oncology, the First hospital Affiliated to School of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.

Abstract:  Vascular endothelial growth factor receptor-1 (VEGFR-1 or Flt-1), a tyrosine kinase receptor, is highly expressed in breast cancer tissues, but near absent in normal breast tissue. While VEGFR-1 expression is associated with poor prognosis of women with breast cancer, it is not clear whether it is involved in the aggressiveness of breast cancer. Thus, the present study examined whether VEGFR-1 activation is associated with the invasiveness of breast cancer. We reported that VEGFR-1 was detected in 60.6% of invasive breast carcinoma tissue sections. In addition, VEGFR-1 expression positively correlated with lymph node-positive tumor status, low expression level of membranous E-cadherin, and high expression levels of N-cadherin and Snail. We found that PlGF-mediated VEGFR-1 activation promoted migration and invasion in MCF-7 (luminal) cells and led to morphologic and molecular changes of epithelial-mesenchymal transition (EMT). This was blocked by the down-regulation of VEGFR-1. Conversely, down-regulation of VEGFR-1 in MDA-MB-231 (post-EMT) cells resulted in morphologic and molecular changes similar to mesenchymal-epithelial transition (MET), and exogenous PlGF could not reverse these changes. Moreover, VEGFR-1 activation led to an increase in nuclear translocation of Snail. Finally, MDA-MB-231 cells expressing shRNA against VEGFR-1 significantly decreased the tumor growth and metastasis capacity in a xenograft model. Histological examination of VEGFR-1/shRNA-expressing tumor xenografts showed up-regulation of E-cadherin and down-regulation of N-cadherin and Snail. These findings suggest that VEGFR-1 may promote breast cancer progression and metastasis, and therapies that target VEGFR-1 may be beneficial in the treatment of breast cancer patients. 

Retracted: No

PubPeer comments:
 Figure 3. Reported to the journal in October 2015. * Green boxes: Three panels in Figure 3B and 3C appear to show an overlap. ![file] , 
 Dear professor, I m so sorry. I haven t paid attention to email recently, I reply to you now. First of all, thank you very much for your comments on my research,I sincerely accept it. It will be helpful for my future work. Then I would like to say that I respect science,and there were no plagiarism and academic fraud involved in this article. Because there are too many figures,and I was a little careless, so I made the mistake when I chose figures, I sincerely accepte your remind.And I sincerely apologize for my careless. I have corrected the mistake as follows. I hope you can give me a chance to correct the mistakes. Thany you! ![file] ![file] , 
 Retraction, 31 August 2022: https: journals.plos.org plosone article?id=10.1371 journal.pone.0274216  Following the publication of this article [1], concerns were raised regarding results presented in multiple figures. Specifically, * In Figure 6A, tumor volume appears to exceed internationally-accepted standards, raising concern about animal welfare and the adherence of the study to animal research ethics standards. * The shRNA and shRNA + PIGF panels for MDA-MB-231 in Figure 3B and the PIGF panel for MDA-MB-231 in Figure 3C appear to partially overlap despite representing different conditions. * The following panels appear similar despite representing different conditions: The u03b2-actin panel for MDA-MB-231 in Figure 3A and lanes 1u20133 of the E-cadherin panel in Fig 4D with the aspect ratio altered. The u03b2-catenin panel in Figure 4E and the Snail (6 hours) panel for MDA-MB-231 in Figure 5. * The following loading control panels appear similar: Lamin B1 in Figure 4D and Lamin B1 for MCF-7 in Figure 5. Lamin B1 in Figure 4E and Lamin B1 for MDA-MB-231 in Figure 5. * No sequence is provided in the article for the control shRNA. The corresponding author acknowledged that they no longer have a record of the control shRNA sequence. The corresponding author stated that mice were observed every day for mental state, food intake, activity, and diameter of the tumor at the injection site. They confirmed that after 30 days, half the mice had lost weight and were exhibiting behavioral changes, and at that point, the experiment was terminated. Data files described as raw tumor and body weight data were provided which indicated that weight loss was observed from day 14 onwards and final tumor weight exceeded 10% body weight in some mice. Concerns regarding tumor volume and animal welfare indicate that the article is not in compliance with PLOSu2019s Animal Research policy. The corresponding author provided raw image data underlying the western blots in Figures 2A, 3A, 4D, 4E, and 5. They acknowledged that the following panels are incorrect and provided replacement data: * The shRNA + PIGF panel for MDA-MB-231 in Figure 3B and the PIGF panel for MDA-MB-231 in Figure 3C. * The u03b2-actin panel for MDA-MB-231 in Figure 3A. * The Snail (6 hours) panel for MDA-MB-231 in Figure 5. In the raw image provided for the Snail (6 hours) panel for MCF-7 in Figure 5, a rectangular area unlike the rest of the background is observed in the shRNA + PIGF lane when color levels are adjusted. The Editors remain concerned about the integrity of this raw image. The corresponding author stated that Lamin B1 loading control was measured for each of the western blot experiments in Figures 4D, 4E, and 5, but that the same Lamin B1 images were reused in preparation of the figures. The correct loading control images corresponding to each experiment were not provided. In light of the above concerns regarding animal welfare which indicate that the article is not in compliance with PLOSu2019s Animal Research policy, and the concerns affecting images in multiple figures which question the reliability of these data, the PLOS ONE Editors retract this article. XZhao did not agree with the retraction and apologizes for the issues with the published article. CL responded but expressed neither agreement nor disagreement with the editorial decision. QN, LH, MM, XZhang, ML, SS, and XZuo either did not respond directly or could not be reached. ,