Inhibition of Estrogen-dependent Tumorigenesis by the Thyroid Hormone Receptor β in Xenograft Models

Association studies suggest that thyroid hormone receptor β (TRβ) could function as a tumor suppressor in breast cancer development, but unequivocal evidence is still lacking. To understand the role of TRβ in breast tumor development, we adopted the gain-of-function approach by stably expressing the THRB gene in a human breast cancer cell line, MCF-7 (MCF-7-TRβ). Parental MCF-7 cells express the estrogen receptor, but not TRs. MCF-7 cells, stably expressing only the selectable marker, the Neo gene, were also generated as control for comparison (MCF-7-Neo cells). Cell-based studies indicate that the estrogen (E2)-dependent growth of MCF-7 cells was inhibited by the expression of TRβ in the presence of the thyroid hormone (T3). In a xenograft mouse model, large tumors rapidly developed after inoculation of MCF-7-Neo cells in athymic mice. In contrast, markedly smaller tumors (98% smaller) were found when MCF-7-TRβ cells were inoculated in athymic mice, indicating that TRβ inhibited the E2-dependent tumor growth of MCF-7 cells. Further detailed molecular analysis showed that TRβ acted to activate apoptosis and decrease proliferation of tumor cells, resulting in inhibition of tumor growth. The TRβ-mediated inhibition of tumor growth was elucidated via down-regulation of the JAK-STAT-cyclin D pathways. This in vivo evidence shows that TRβ could act as a tumor suppressor in breast tumorigenesis. The present study provides new insights into the role of TR in breast cancer.