Autoimmune thyroiditis promotes breast cancer progression: exploratory role of thyroid hormone receptor beta signaling disruption

The association between autoimmune thyroiditis (AITD) and breast cancer has been frequently reported in epidemiological studies. However, the underlying mechanisms remain unclear, particularly regarding whether AITD-related antibodies contribute to breast cancer progression. We hypothesized that thyroid hormone receptor beta (THRβ) autoantibodies may mediate this association by disrupting THRβ signaling in breast cancer cells. An AITD-breast cancer comorbidity model was established by simultaneously inducing EAT and orthotopically transplanting breast cancer cells in NOD/ShiLtJ mice. Histological evaluation (H&E staining), ELISA, and immunohistochemistry were used to assess thyroiditis induction and tumor characteristics. In vitro, 5-ethynyl-2'-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), scratch, and Transwell assays were performed to evaluate the effects of THRβ-reactive antibody on the proliferation and migration of breast cancer cells. The antagonistic effect of the selective THRβ agonist Resmetirom was also examined. Additionally, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to investigate THRβ expression and its prognostic relevance in breast cancer tissues. In vivo experiments demonstrated that the AITD mouse model exhibited significantly elevated serum levels, accompanied by increased tumor formation rate and proliferative activity of breast cancer cells. In vitro, directly promoted proliferation and migration of MDA-MB-231 and MCF-7 cells, while the selective THRβ agonist Resmetirom effectively counteracted these effects. Bioinformatics analysis revealed that THRβ expression was downregulated in breast cancer tissues, and higher expression was associated with improved disease-free survival. This study suggests that THRβ-reactive antibody may promote breast cancer progression by disrupting THRβ signaling, indicating a mechanistic link between AITD and breast cancer comorbidity. Targeting THRβ signaling with agents such as Resmetirom may hold therapeutic potential in this immune-related oncologic context.