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Citations to this article

SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer
Chu-An Wang, … , J. Chuck Harrell, Heide L. Ford
Chu-An Wang, … , J. Chuck Harrell, Heide L. Ford
Published April 2, 2012
Citation Information: J Clin Invest. 2012;122(5):1895-1906. https://doi.org/10.1172/JCI59858.
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Research Article Oncology Article has an altmetric score of 12

SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer

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Abstract

An association between lymph node metastasis and poor prognosis in breast cancer was observed decades ago. However, the mechanisms by which tumor cells infiltrate the lymphatic system are not completely understood. Recently, it has been proposed that the lymphatic system has an active role in metastatic dissemination and that tumor-secreted growth factors stimulate lymphangiogenesis. We therefore investigated whether SIX1, a homeodomain-containing transcription factor previously associated in breast cancer with lymph node positivity, was involved in lymphangiogenesis and lymphatic metastasis. In a model in which human breast cancer cells were injected into immune-compromised mice, we found that SIX1 expression promoted peritumoral and intratumoral lymphangiogenesis, lymphatic invasion, and distant metastasis of breast cancer cells. SIX1 induced transcription of the prolymphangiogenic factor VEGF-C, and this was required for lymphangiogenesis and lymphatic metastasis. Using a mouse mammary carcinoma model, we found that VEGF-C was not sufficient to mediate all the metastatic effects of SIX1, indicating that SIX1 acts through additional, VEGF-C–independent pathways. Finally, we verified the clinical significance of this prometastatic SIX1/VEGF-C axis by demonstrating coexpression of SIX1 and VEGF-C in human breast cancer. These data define a critical role for SIX1 in lymphatic dissemination of breast cancer cells, providing a direct mechanistic explanation for how VEGF-C expression is upregulated in breast cancer, resulting in lymphangiogenesis and metastasis.

Authors

Chu-An Wang, Paul Jedlicka, Aaron N. Patrick, Douglas S. Micalizzi, Kimberly C. Lemmer, Erin Deitsch, Matias Casás-Selves, J. Chuck Harrell, Heide L. Ford

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2009 Total
Citations: 1 8 4 4 5 10 7 5 1 6 7 4 5 5 1 73
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Citations to this article (74)

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Li J, Yan Z, Ma J, Chu Z, Li H, Guo J, Zhang Q, Zhao H, Li Y, Wang T
Frontiers in Oncology 2022
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Annals of translational medicine 2022
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Frontiers in Oncology 2021
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T Yu, J Song, H Zhou, T Wu, Z Liang, P Du, CY Liu, G Wang, L Cui, Y Liu
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S Sahoo, A Mishra, H Kaur, K Hari, S Muralidharan, S Mandal, MK Jolly
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Q He, Z Lin, Z Wang, W Huang, D Tian, M Liu, L Xia
Oncogene 2020
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Oncogene 2020

Six1 Overexpression Promotes Glucose Metabolism and Invasion Through Regulation of GLUT3, MMP2 and Snail in Thyroid Cancer Cells


C Yang, W Xu, J Gong, F Chai, D Cui, Z Liu
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S Zheng, L Yang, Y Zou, J Liang, P Liu, G Gao, A Yang, H Tang, X Xie
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B Dong, M Yi, S Luo, A Li, K Wu
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