Cytoplasmic Localization of Thyroid Hormone Receptor (TR) Alpha and Nuclear Expression of Its Isoform TR & alpha;2 Determine Survival in Breast Cancer in Opposite Ways

The aim of this retrospective study was to assess the respective prognostic values of cytoplasmic and nuclear TRa, TRa1, and TRa2 expression in breast cancer (BC) tissue samples and correlate the results with clinico-pathological parameters. In 249 BC patients, the expression patterns of general TRa and the a1 and a2 isoforms were evaluated via immuno-histochemistry. Prognosis-determining aspects were calculated via univariate, as well as multivariate, analysis. Univariate Cox-regression analysis revealed no association between nuclear TRa expression and overall survival (OS) (p = 0.126), whereas cytoplasmic TRa expression was significantly correlated with a poor outcome for both OS (p = 0.034) and ten-year survival (p = 0.009). Strengthening these results, cytoplasmic TRa was found to be an independent marker of OS (p = 0.010) when adjusted to fit clinico-pathological parameters. Analyses of the TRa-subgroups revealed that TRa1 had no prognostic relevance, whereas nuclear TRa2 expression was positively associated with OS (p = 0.014), ten-year survival (p = 0.029), and DFS (p = 0.043). Additionally, nuclear TRa2 expression was found to be an independent positive prognosticator (p = 0.030) when adjusted to fit clinico-pathological parameters. Overall, our results support the hypothesis that subcellular localization of TRa and its isoforms plays an important role in the carcinogenesis and prognosis of breast cancer. Cytoplasmic TRa expression correlates with more aggressive disease progression, whereas nuclear TRa2 expression appears to be a protective factor. These data may help us to prioritize high-risk BC subgroups for possible targeted tumor therapy.