Thyroid Hormone Receptor ß / AR Interplay in Prostate Cancer

Many patients with prostate cancer develop androgen-independent tumor growth, which is referred to as castration-resistant prostate cancer (CRPC). In these patients, activation of the androgen receptor (AR) in the tumors no longer requires androgen stimulation, and therapy with androgen inhibitors becomes ineffective. It is therefore important to identify new additional treatment options for these patients. Elevated levels of the thyroid hormone triiodothyronine (T3) have long been associated with a poorer prognosis of cancer. Based on studies in which the T3-binding protein CRYM was identified as a decisive factor for the availability of T3 in prostate cancer cells, the focus has now shifted to the signaling pathway driven by T3. The focus here is on the thyroid hormone receptor ß (TRß) as a key signaling molecule. The research group led by Prof. Lukas Kenner and Assoc. Prof. Brigitte Hantusch found that TRß is increasingly expressed in more aggressive forms of prostate cancer and is associated with a poorer prognosis. In vitro experiments have shown that T3 drives the proliferation of prostate cancer cells and accomplishes this by enhancing androgen receptor (AR)-driven gene expression. In the project funded by the FWF, the researchers aim to investigate in detail whether and how TRß promotes the growth of prostate cancer cells and whether the essential processes are controlled autonomously or in cooperation with the AR. Various experimental approaches will be used to clarify the extent to which the two hormone-driven signaling pathways overlap, whether there is reciprocal regulation, or whether the two receptors may even cooperate directly with each other. To this end, genetic and pharmacological switches for these receptors are used and the respective altered gene and protein expressions are measured. These data provide direct information about the hierarchy and interaction of TRß and AR-driven processes, which generally show how hormones are effective in the body. The resulting molecular insights will be validated by analysis of histological tumor samples, and correlations will be calculated using patients` clinical parameters to identify predictive markers of disease progression and therapeutic targets. Translated with DeepL.com (free version) This project will contribute to the understanding of hormone-dependent growth of prostate cancer to improve prognostic approaches and potentially lead to the development of innovative therapeutic strategies.