The nuclear corepressor 1 and the thyroid hormone receptor β suppress breast tumor lymphangiogenesis.
Vascular Endotelial Growth Factors C and D (VEGF-C and VEGF-D) are crucial regulators of lymphangiogenesis, a main event in the metastatic spread of breast cancer tumors. Although inhibition of lymphangiogenic gene expression might be a useful therapeutic strategy to restrict the progression of cancer, the factors involved in the transcriptional repression of these genes are still unknown. We have previously shown that Nuclear Receptor Corepressor 1 (NCoR) and the thyroid hormone receptor β1 (TRβ) inhibit tumor invasion. Here we show that these molecules repress VEGF-C and VEGF-D gene transcription in breast cancer cells, reducing lymphatic vessel density and sentinel lymph node invasion in tumor xenografts. The clinical significance of these results is stressed by the finding that NCoR and TRβ transcripts correlate negatively with those of the lymphangiogenic genes and the lymphatic vessel marker LYVE-1 in human breast tumors. Our results point to the use of NCoR and TRβ as potential biomarkers for diagnosis or prognosis in breast cancer and suggest that further studies of these molecules as potential targets for anti-lymphangiogenic therapy are warranted.
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain.
Olaia
O
Martínez-Iglesias
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Universidad Autónoma de Madrid, Spain.
David
D
Olmeda
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain.
Elvira
E
Alonso-Merino
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain.
Sara
S
Gómez-Rey
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain.
Ana M
AM
González-López
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain.
Enrique
E
Luengo
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, Universidad Autónoma de Madrid, Spain.
María S
MS
Soengas
Departamento de Anatomía Patológica, Hospital Universitario Ramón y Cajal, Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Universidad de Alcalá, Spain.
José
J
Palacios
Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Javier
J
Regadera
Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Spain.
Ana
A
Aranda
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D061986:MCF-7 Cells; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D014158:Transcription, Genetic; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics
C119248:LYVE1 protein, human; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D037042:Thyroid Hormone Receptors beta; C467486:VEGFC protein, human; C579459:VEGFD protein, human; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D033921:Vesicular Transport Proteins
VEGFs; breast cancer; lymphangiogenesis; nuclear receptor corepressor 1; thyroid hormone receptor beta 1