title: SIX1 induces lymphangiogenesis and metastasis via upregulation of VEGF-C in mouse models of breast cancer.
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.affiliation: Program in Molecular Biology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Chu-An
authors.initials: CA
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Patrick
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Micalizzi
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Lemmer
authors.forename: Erin
authors.initials: E
authors.lastname: Deitsch
authors.forename: Matias
authors.initials: M
authors.lastname: Casás-Selves
authors.forename: J Chuck
authors.initials: JC
authors.lastname: Harrell
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D042583:Lymphangiogenesis; D008207:Lymphatic Metastasis; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic; D047368:Tumor Burden; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C099236:SIX1 protein, human; D042582:Vascular Endothelial Growth Factor C