Thyroid Hormone T3 Induces DNA Damage Response in Breast Cancer Cells

TL;DR

Thyroid hormone T3 causes temporary DNA damage in breast cancer cells, which might explain why thyroid hormone therapy is linked to higher cancer recurrence risk.

Contribution

This study reveals that T3 induces a transient DNA damage response in breast cancer cells, offering a novel mechanistic link to clinical observations.

Findings

T3 exposure upregulates DNA repair genes like RAD51 and activates DDR markers such as γH2AX and 53BP1.

The DNA damage response is transient and returns to baseline after 48 hours.

T3 promotes cell proliferation at low concentrations but inhibits growth at higher concentrations.

Abstract

Thyroid hormones (THs) regulate metabolism, proliferation, and genomic stability. Clinical studies have linked levothyroxine therapy with higher Oncotype DX Recurrence Scores in breast cancer (BC), suggesting a potential effect of thyroid hormone signaling on genomic risk. Here, we investigated the impact of triiodothyronine (T3) on DNA damage and repair pathways in estrogen receptor-positive T47D breast cancer and non-tumorigenic MCF10A cells. RNA sequencing revealed significant upregulation of RAD51 and enrichment of DNA repair pathways following 24 h T3 exposure. Consistently, T3 increased γH2AX and 53BP1 nuclear foci, indicating transient activation of the DNA damage response (DDR). These effects were transient, returning to baseline after 48 h, suggesting cellular adaptation. T3 also enhanced proliferation at 10 μM but inhibited growth at higher concentrations. Our findings indicate that acute exposure to T3 induces transient genomic stress, providing a potential mechanistic basis for the observed association between thyroid hormone therapy and increased BC recurrence risk.

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