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 (TRβ) was one of the most differentially expressed
nuclear receptors in group 5 compared to other groups. TRβ low expressing patients were associated with poor outcome. We evaluated the role of TRβ in
triple-negative breast cancer cell lines representing group 5
tumors. Knockdown of TRβ increased soft
agar colony and reduced sensitivity to
docetaxel and
doxorubicin treatment.
Docetaxel or
doxorubicin long-term cultured cell lines also expressed decreased TRβ
protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TRβ knockdown cells. Inhibitors of cAMP or PKA, in combination with
doxorubicin further enhanced cell apoptosis and restored sensitivity to
chemotherapy. TRβ-specific agonists enhanced TRβ expression, and further sensitized cells to both
docetaxel and
doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and
caspase 3. TRβ represents a novel
nuclear receptor target in
triple-negative breast cancer; low TRβ levels were associated with enhanced resistance to both
docetaxel and
doxorubicin treatment. TRβ-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TRβ's effects on response to
chemotherapy.