Targeting thyroid hormone receptor beta in triple-negative breast cancer

The purpose of this study was to discover novel nuclear receptor targets in triple-negative breast cancer. Expression microarray, Western blot, qRT-PCR analyses, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, and statistical analysis were performed in this study. We performed microarray analysis using 227 triple-negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TR beta) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TR beta low expressing patients were associated with poor outcome. We evaluated the role of TR beta in triple-negative breast cancer cell lines representing group 5 tumors. Knockdown of TR beta increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TR beta protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TR beta knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TR beta-specific agonists enhanced TR beta expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. TR beta represents a novel nuclear receptor target in triple-negative breast cancer; low TR beta levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TR beta-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TR beta's effects on response to chemotherapy.