Loss of tyrosine phosphorylation at Y406 abrogates the tumor suppressor functions of the thyroid hormone receptor β

Abstract

We have recently identified that phosphorylation at tyrosine (Y)406 is critical for the tumor suppressor functions of the thyroid hormone receptor β1 (TRβ) in a breast cancer line. However, still unclear is whether the critical tumor suppressor role of phosphorylated Y406 of TRβ is limited to only breast cancer cells or could be extended to other cell types. In the present studies, we addressed this question by stably expressing TRβ, a mutated TRβ oncogene (PV), or a TRβ mutated at Y406 (TRβY406F) in rat PCCL3 thyroid follicular cells and evaluated their tumor characteristics in athymic mice with elevated thyroid stimulating hormone. PCCL3 cells stably expressing PV (PCCL3-PV), TRβY406F (PCCL3-TRβY406F), or vector only (PCCL3-Neo) developed tumors with sizes in the rank order of TRβY406F>PV = Neo, whereas PCCL3 cells expressing TRβ (PCCL3-TRβ) barely developed tumors. As evidenced by markedly elevated Ki67, cyclin D1, and p-Rb protein abundance, proliferative activity was high in PV and TRβY406F tumors, but low in TRβ tumors. These results indicate that TRβ acted as a tumor suppressor in PCCL3 cells, whereas TRβY406F and PV had lost tumor suppressor activity. Interestingly, TRβY406F tumors had very low necrotic areas with decreased TNFα-NFκB signaling to lower apoptotic activity. In contrast, PV tumors had prominent large necrotic areas, with no apparent changes in TNFα-NFκB signaling, indicating distinct oncogenic activities of mutant PV and TRβY406F. Thus, the present studies uncovered a novel mechanism by which TRβ could function as a tumor suppressor through modulation of the TNFα-NFκB signaling. © 2016 Wiley Periodicals, Inc.

Subcellular Distribution of Thyroid Hormone Receptor Beta in Ovarian Cancer

“…Applying the receptLoss algorithm, the authors highlighted that loss of THRB gene expression was linked to favorable prognosis in endometrial cancer [ 21 ]. In addition, TR beta mutations have been demonstrated to exert tumor-promoting activity in different types of cells [ 22 ]. Though the THRB mutational status of tissue samples studied in the current analysis is not known, human tumors in general have been reported to carry multiple TR mutations that might influence both the biologic and prognostic meaning of TR beta [ 23 ].…”

Triiodothyronine lowers the potential of colorectal cancer stem cells in vitro

“…It was suggested that THRβ1 acts as tumor suppressor in a number of cancers and one of the proposed mechanism relay on upregulation of the nuclear receptor co-repressor 1 and suppression of invasion, tumor growth, and metastasis in human as it was demonstrated for hepatocellular carcinomas ( 35 ) and neuroblastomas ( 36 ). In addition, breast cancer mammospheres presented reduced tumorigenesis upon stimulation of THRβ1 ( 37 ). The possible mechanisms are downregulation of cyclin D1 expression and modulation of the TNFα-NFκB signaling ( 23 , 37 ).…”

“…In addition, breast cancer mammospheres presented reduced tumorigenesis upon stimulation of THRβ1 ( 37 ). The possible mechanisms are downregulation of cyclin D1 expression and modulation of the TNFα-NFκB signaling ( 23 , 37 ). Certain of the present results supported these previous observations since it was observed that the expression of THRβ1 receptor was significantly lower in HT29 cells following T3 treatment.…”

The TSH/Thyroid Hormones Axis and Breast Cancer

“…TRβ, in co-operation with transcription partner RXRβ, directly represses the transcription of pro-tumorigenic β-catenin in thyroid and cervical cancer cells [40]. The phosphorylation of TRβ at tyrosine 406 seems to be a pre-requisite for its tumor-suppressing function [41]. Cells transfected with a TRβ mutated at position 406 (phenylalanine replacing the native tyrosine) showed a growth ability in rats that was equivalent to cells transfected with an empty vector, while xenografts of cells transfected with a wild-type TRβ were deficient in their growth.…”