Thyroid cancer is the most common endocrine
malignancy, and the global incidence has increased rapidly over the past few decades.
Anaplastic thyroid cancer (ATC) is highly aggressive, dedifferentiated, and patients have a median survival of fewer than 6 months. Oncogenic alterations in ATC include aberrant
phosphoinositide 3 kinase (PI3K) signaling through
receptor tyrosine kinase (RTK) amplification, loss of
phosphoinositide phosphatase expression and function, and
protein kinase B (Akt) amplification. Furthermore, the loss of expression of the
tumor suppressor
thyroid hormone receptor beta (TRβ) is strongly associated with ATC. TRβ is known to suppress PI3K in
follicular thyroid cancer and
breast cancer by binding to the PI3K regulatory subunit p85α. However, the role of TRβ in suppressing PI3K signaling in ATC is not completely delineated. Here we report that TRβ indeed suppresses PI3K signaling in ATC cell lines through unreported genomic mechanisms, including a decrease in RTK expression and an increase in
phosphoinositide and Akt
phosphatase expression. Furthermore, the reintroduction and activation of TRβ in ATC cell lines enables an increase in the efficacy of the competitive PI3K inhibitors
LY294002 and
buparlisib on cell viability, migration, and suppression of PI3K signaling. These findings not only uncover additional
tumor suppressor mechanisms of TRβ but shed light on the implication of TRβ status and activation on inhibitor efficacy in ATC
tumors.