Endocrine Abstracts

Lymphangiogenesis is a very important event in breast cancer development and VEGF-C and D factors play an essential role in this process. Tumoral invasion of lymphatic vessels facilitates metastasis formation and is a bad pronostic marker in this pathology. Although the thyroid hormone receptors (TRs) are ubiquitously expressed in normal tissues, inactivation and mutations of the TRβ gene are usual events in breast cancer, suggesting that the native receptors could act as tumor suppressors. Indeed, we have shown that expression of TRβ in breast cancer cells reduces tumor growth, invasion and metastasis development in nude mice. Now, we have examined a possible role of TRβ as an inhibitor of lymphangiogenesis using the highly metastatic cell line MDA-MB-468 (MDA). We observed lower levels of VEGF-C and VEGF-D mRNA in MDA cells stably expressing TRβ (MDA-TRβ) than in parental cells, and the treatment with the thyroid hormone T3 further reduced these levels. In transient transfection assays TRβ expression and T3 treatment decreased the activity of the VEGF-C promoter, showing that the receptor represses VEGF-C transcription. As expected, VEGF-C and D transcripts were lower in tumors originated by the inoculation of MDA-TRβ cells in nude mice than in those formed by parental cells. Furthermore, the expression of the lymphatic marker Lyve1 demonstrated a lower number of vessels in tumors originated by the MDA-TRβ cells. The expression of VEGF-C and D, as well as the number of lymphatic vessels, was however higher in tumors grown in hypothyroid nude mice, in accordance with previous our results showing that host hypothyroidism increases invasion and metastasis development by breast cancer cells.

These results demonstrate that TRβ reduces lymphangiogenesis, repressing VEGF-C and VEGF-D gene expression, and this repression could explain, at least in part, the actions of this receptor as a suppressor of metastatic growth.