Cytoplasmic versus nuclear THR alpha expression determines survival of ovarian cancer patients

Abstract

Purpose Thyroid hormone receptors (THR) have manifold functions and are involved in the carcinogenesis of several tumor types. Within this study, we aimed to investigate the expression pattern (nuclear versus cytoplasmic) of the THR alpha and its impact on patients survival in ovarian cancer (OvCa). Methods The presence of the thyroid hormone receptors THRα, THRα1 and − 2 was investigated in 156 ovarian cancer samples using immunohistochemistry (IHC) using semi-quantitative immunoreactivity (IR) scores and correlated with clinical, pathological data, subtype of ovarian cancer, clinical data, staining of 20 already described OvCa marker proteins and overall survival (OS). Results Among all subtypes of OvCa, clear cell carcinomas showed the highest THRα expression. Furthermore, nuclear THRα was associated with a reduced survival in this subtype. However, nuclear expressed THRα1 turned out to be a positive prognosticator for all subtypes of OvCa patients. Nuclear THRα2 is a positive prognosticator for OvCa patients of the serous subtype. In contrast, cytoplasmic expression THRα2 was associated with a reduced OS in all subtypes of OvCa patients; while, cytoplasmic expression of THRα1 is associated with reduced OS in mucinous OvCa patients only. In addition, THRα expression correlates with gonadotropin receptors, steroid hormone receptors, TA-MUC1 and glycodelin. Conclusion Depending on nuclear or cytoplasmic expression, our study shows that THRα and its isoforms 1 and 2 provide different prognostic information for ovarian cancer patients. Further investigations should analyze if THRs may represent new endocrine targets for the treatment of ovarian cancer.

Cytoplasmic Localization of RXRα Determines Outcome in Breast Cancer

“…However, recent data on other nuclear receptors in cancer research indicate that the prognostic value of nuclear receptors depends on their subcellular localization [24]. Consistently with our findings, Ditsch et al demonstrated that there is a direct link between the nuclear localization of THR and increased OS in epithelial ovarian cancer [22]. However, THR has been identified to show cancer-promoting activities during BC development [24].…”

“…NRs are activated by binding to lipophilic metabolites and mainly function as transcription factors in the nucleus [19,20]. Novel literature demonstrates that, besides the well-established NR, other receptors, including the retinoid X receptor (RXR), thyroid hormone receptors (THRs) and vitamin D receptor (VDR), play a significant role in the pathophysiology not only of BC but also of other cancer entities [21][22][23]. Studies on the role of NR in distinct intracellular compartments indicate a specific prognostic value, depending on the subcellular localization [24].…”

“…Czogalla et al demonstrated a direct link between the cytoplasmic localization of VDR and impaired overall survival (OS) in ovarian cancer [25]. In the case of THR, high nuclear localization was reported to be a positive predictive factor for OS in epithelial ovarian cancer [22]. In contrast, nuclear THR has been identified to have cancer-promoting activities in BC development [24].…”

Application of the Interaction between Tissue Immunohistochemistry Staining and Clinicopathological Factors for Evaluating the Risk of Oral Cancer Progression by Hierarchical Clustering Analysis: A Case-Control Study in a Taiwanese Population

“…Besides, our study raised an interesting issue of localization of IHC staining. In previous studies of ovarian cancer, different localizations of thyroid hormone receptors and αvβ3 integrin demonstrated different nuclear and non-nuclear signaling pathway for cancerogenesis [ 40 , 41 ]. The translocation of transmembrane proteins from the cell membrane to the nucleus may be another crucial mechanism [ 42 ].…”

β-Lactoglobulin and Glycodelin: Two Sides of the Same Coin?

“…For example, it was found that the presence of Gd was indicative of a better prognosis in endometrial cancer whereas the presence of the immunosuppressive Gd-A indicated a poorer overall survival rate ( Lenhard et al, 2013 ). In ovarian cancer too, the presence of Gd-A has a positive correlation with other markers that indicate a poorer outcome ( Scholz et al, 2012 ; Ditsch et al, 2020 ). The presence of Gd can be detected by immunohistological staining of tissue biopsies and also in serum samples but is just one of many proposed neoplastic markers, the clinical significance of which, if any, as a cancer marker remains to be established.…”