Abstract
Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been shown to antagonize THRα1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRα1 splice variant and the entire receptor, THRα, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRα1 or THRα did not cause substantial anti-proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone’s cytotoxic effect in breast cancer cell lines are independent of THRα or THRα1 antagonism. Further, the depletion of THRα or THRα1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone’s anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents.
Highlights
THRα and THRα1 overexpression is associated with shorter overall survival in breast cancer patients in The Cancer Genome Atlas (TCGA) dataset
Given a growing body of literature which supports the role of THRα and its splice variants as prognostic biomarkers for overall survival among women with breast cancer, we investigated the prognostic significance of THRα and THRα1 expression in the well-annotated TCGA breast cancer cohort
When dichotomized into low and high expression of THRα and THRα1, there was no difference in overall survival in patients with breast cancer, Figure 2
Summary
The specific role of each thyroid receptor subtype in various cancers has yet to be elucidated[15,16], likely due to the complexity of both genomic and non-genomic actions of THRs2,17, differential expression in different human tissues[18], as well as the potential for cross-talk with estrogen signaling pathways[19,20,21]. The prognostic data suggests that modulation of the THRα pathway may have therapeutic potential in breast and other cancers[15,23,26] if specific isoforms can be targeted In support of this premise, modulation of THRα1 isoform expression in adipose derived stem cells affects expression of genes governing cell cycle and proliferation[27]. We sought to evaluate the anti-cancer effects of dronedarone and to characterize the potential of targeting THRα1 in human breast cancer models
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