The Thyroid Hormone Receptor-RUNX2 Axis: A Novel Tumor Suppressive Pathway in Breast Cancer.

Metastatic breast cancer is refractory to conventional therapies and is an end-stage disease. RUNX2 is a transcription factor that becomes oncogenic when aberrantly expressed in multiple tumor types, including breast cancer, supporting tumor progression and metastases. Our previous work demonstrated that the thyroid hormone receptor beta (TRß) inhibits RUNX2 expression and tumorigenic characteristics in thyroid cells. As TRß is a tumor suppressor, we investigated the compelling question whether TRß also regulates RUNX2 in breast cancer. The Cancer Genome Atlas indicates that TRß expression is decreased in the most aggressive basal-like subtype of breast cancer. We established that modulated levels of TRß results in corresponding changes in the high levels of RUNX2 expression in metastatic, basal-like breast cells. The MDA-MB-231 triple-negative breast cancer cell line exhibits low expression of TRß and high levels of RUNX2. Increased expression of TRß decreased RUNX2 levels. The thyroid hormone-mediated suppression of RUNX2 is TRß specific as TRα overexpression failed to alter RUNX2 expression. Consistent with these findings, knockdown of TRß in non-tumor MCF10A mammary epithelial-like cells results in an increase in RUNX2 and RUNX2 target genes. Mechanistically, TRß directly interacts with the proximal promoter of RUNX2 through a thyroid hormone response element to reduce promoter activity. The TRß suppression of the oncogene RUNX2 is a signaling pathway shared by thyroid and breast cancers. Our findings provide a novel mechanism for TRß-mediated tumor suppression in breast cancers. This pathway may be common to many solid tumors and impact treatment for metastatic cancers.

Thyroid Hormone Receptor ß Suppression of RUNX2 Is Mediated by Brahma-Related Gene 1-Dependent Chromatin Remodeling.

Thyroid hormone receptor ß (TRß) suppresses tumor growth through regulation of gene expression, yet the associated TRß-mediated changes in chromatin assembly are not known. The chromatin ATPase brahma-related gene 1 (BRG1; SMARCA4), a key component of chromatin-remodeling complexes, is altered in many cancers, but its role in thyroid tumorigenesis and TRß-mediated gene expression is unknown. We previously identified the oncogene runt-related transcription factor 2 (RUNX2) as a repressive target of TRß. Here, we report differential expression of BRG1 in nonmalignant and malignant thyroid cells concordant with TRß. BRG1 and TRß have similar nuclear distribution patterns and significant colocalization. BRG1 interacts with TRß, and together, they are part of the regulatory complex at the RUNX2 promoter. Loss of BRG1 increases RUNX2 levels, whereas reintroduction of TRß and BRG1 synergistically decreases RUNX2 expression. RUNX2 promoter accessibility corresponded to RUNX2 expression levels. Inhibition of BRG1 activity increased accessibility of the RUNX2 promoter and corresponding expression. Our results reveal a mechanism of TRß repression of oncogenic gene expression: TRß recruitment of BRG1 induces chromatin compaction and diminishes RUNX2 expression. Therefore, BRG1-mediated chromatin remodeling may be obligatory for TRß transcriptional repression and tumor suppressor function in thyroid tumorigenesis.