The nuclear corepressor 1 and the thyroid hormone receptor β suppress breast tumor lymphangiogenesis

// Olaia Martinez-Iglesias 1 , David Olmeda 2 , Elvira Alonso-Merino 1 , Sara Gomez-Rey 1 , Ana M. Gonzalez-Lopez 1 , Enrique Luengo 1 , Maria S. Soengas 2 , Jose Palacios 3 , Javier Regadera 4 , Ana Aranda 1 1 Instituto de Investigaciones Biomedicas “Alberto Sols”, Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, Spain 2 Molecular Oncology Programme, Centro Nacional de Investigaciones Oncologicas, Universidad Autonoma de Madrid, Spain 3 Departamento de Anatomia Patologica, Hospital Universitario Ramon y Cajal, Instituto de Investigacion Sanitaria Ramon y Cajal (IRYCIS), Universidad de Alcala, Spain 4 Departamento de Anatomia, Histologia y Neurociencia, Facultad de Medicina, Universidad Autonoma de Madrid, Spain Correspondence to: Ana Aranda, email: aaranda@iib.uam.es Olaia Martinez Iglesias, email: omartinez@iib.uam.es Keywords: thyroid hormone receptor beta 1, nuclear receptor corepressor 1, lymphangiogenesis, VEGFs, breast cancer Received: September 01, 2016      Accepted: October 22, 2016      Published: October 27, 2016 ABSTRACT 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.