Thyroid hormone receptor beta is an oncogene in triple-negative subtype of breast cancer
Date of Award
Master of Medical and Health Science by Research
School of Medical and Health Sciences
Over the past decades, numerous targeted therapies have been added to the breast cancer (BC) treatment armamentarium, resulting in an impressive 90% survival rate. Nevertheless, there remain several unmet clinical issues in the 10% of BC-patients who are diagnosed with aggressive subtypes of BC, such as triple-negative BC (TNBC). TNBCs are highly metastatic, carry a poor prognosis and, due to a lack of targetable receptors, are non-responsive to standard targeted therapies used to treat other BC subtypes. Therefore, there is an urgent need for the novel targeted therapies for TNBC patients to improve their survival by identifying novel drug targets.
Nuclear receptors (NRs) have been regarded as an ideal drug target for cancer therapy owing to their easy druggability and ubiquitous expression, particularly in hormone dependent cancers. In BC, therapeutic exploitation of Estrogen, and more recently, the androgen receptor has yielded impressive results. As a result, more research efforts are being put into identifying alternate NRs for novel BC therapy in TNBCs. In recent studies, Thyroid hormone receptor beta (TRβ) has emerged as a potential druggable NR for treating TNBC. However, due to the contradictory findings published in the literature, its definitive functional role in BC is elusive.
This thesis presents substantial evidence supporting an oncogenic function of TRβ in TNBC, by employing in vitro loss-of-function studies using established BC cell lines. The oncogenic potential of TRβ is further confirmed by Kaplan-Meier survival analysis of publicly available BC patient data where a higher TRβ level was found to be significantly associated with poor prognosis in ER-negative BC patients. The Gene Ontology pathway analysis of TRβ co-expressed genes showed enrichment of biological processes typically found in aggressive cancers, further corroborating the BC cell line and clinical data. The TRβ regulates various cancer hallmarks in TNBC cells, including proliferation and migration. Depletion of TRβ mRNA by short hairpin RNA (shRNA) lentivirus transduction significantly reduced cell proliferation and migration. The TRβ was required in the synthesis phase (S-phase) of the cell cycle. Furthermore, preliminary findings suggested a requirement for TRβ in maintaining a cancer stem-cell population in TNBC cells. These findings collectively suggested that TRβ gene is essential for TNBC cell growth and that anti-TRβ therapeutics may be helpful to TNBC patients.
Access to this thesis has been embargoed until 12th May 2028.
Singh, M. (2023). Thyroid hormone receptor beta is an oncogene in triple-negative subtype of breast cancer. https://doi.org/10.25958/s2gf-r222