Cytoplasmic Localization of Thyroid Hormone Receptor (TR) Alpha and Nuclear Expression of Its Isoform TRα2 Determine Survival in Breast Cancer in Opposite Ways

SIMPLE SUMMARY: There is evidence of a link between breast cancer and thyroid disease. Patients with thyroid dysfunction have an increased incidence of breast cancer compared to healthy women. Therefore, the aim of this study was to evaluate the relevant prognostic value of nuclear and cytoplasmic thyroid receptor (TR) alpha expression and its α1 and α2 isoforms in breast cancer. TRα expression was found to play a contradictory role in BC prognosis depending on its intracellular localization: our results show that TRα and TRα2 expression play different prognostic roles depending on their subcellular localization. Cytoplasmic TRα was a negative prognosticator, whereas nuclear TRα2 expression was positively associated with overall survival. This study highlights the need to further investigate the behavior of TR depending on their intracellular localization. The significance of their subcellular expression and interaction with other members of the nuclear receptor family needs to be elucidated to find new treatment options for breast cancer in the future. ABSTRACT: The aim of this retrospective study was to assess the respective prognostic values of cytoplasmic and nuclear TRα, TRα1, and TRα2 expression in breast cancer (BC) tissue samples and correlate the results with clinico-pathological parameters. In 249 BC patients, the expression patterns of general TRα and the α1 and α2 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 TRα expression and overall survival (OS) (p = 0.126), whereas cytoplasmic TRα 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 TRα was found to be an independent marker of OS (p = 0.010) when adjusted to fit clinico-pathological parameters. Analyses of the TRα-subgroups revealed that TRα1 had no prognostic relevance, whereas nuclear TRα2 expression was positively associated with OS (p = 0.014), ten-year survival (p = 0.029), and DFS (p = 0.043). Additionally, nuclear TRα2 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 TRα and its isoforms plays an important role in the carcinogenesis and prognosis of breast cancer. Cytoplasmic TRα expression correlates with more aggressive disease progression, whereas nuclear TRα2 expression appears to be a protective factor. These data may help us to prioritize high-risk BC subgroups for possible targeted tumor therapy.