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.This work was supported by Grants: BFU2014-53610-P and SAF2015-71878-REDT from Ministerio de Economía y Competitividad; S2011/BMD-2328, from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos III (to A.A), by a Grant from the European Thyroid Association (to O.M-I), by grants RD120036/0064 from Instituto de Salud Carlos III (to J.P) and SAF2014-56868-R (to M.S.S). M.S.S is also funded by the Asociación Española Contra el Cancer (AECC) and by the Melanoma Research Alliance (MRA). This work is partially supported by FEDER funds. O.M.I is supported by an AECC contract