Exposure to hypothyroid serum alters expression of oncogenes and tumor suppressors in preneoplastic breast cells.

Abstract

Introduction: Hypothyroidism is the most prevalent thyroid disorder, whereas breast cancer (BC) is the most common malignancy inwomen. The association between hypothyroidism and BC remains unclear, and clinical studies provide conflicting data, suggesting thathypothyroidism may increase, reduce, or have no effect on BC risk. We hypothesised that exposure of mammary cells to hypothyroidserum triggers transcriptional reprogramming that may influence their future malignant potential.

Material and methods: Serum samples were collected from female patients with hypothyroidism (group H) and healthy volunteers (control group C). The preneoplastic breast epithelial cell line MCF10AT was cultured in the presence of serum H or serum C, with or withoutsupplementation with 3,5,3'-triiodothyronine (T3). Whole‑transcriptome profiling was performed using the Clariom™ S Assay (ThermoFisher Scientific, Waltham, MA, USA), and validation was conducted using quantitative polymerase chain reaction (qPCR). Transcriptomicdata from the Cancer Genome Atlas BRCA cohort were used to evaluate gene expression patterns in breast tumors.

Results: Microarray analysis revealed altered expression of 301 genes, including 185 upregulated and 116 downregulated genes. More than half of the genes with an false discovery rate (FDR) < 0.05 showed consistent directionality of expression in both breast tumors and premalignant MCF10AT cells exposed to hypothyroid serum. Exposure of MCF10AT cells to hypothyroid serum markedly inducedexpression of well‑recognized BC oncogenes (including AGR2 and KRT14), while concurrently reducing expression of tumor suppressors(e.g. ACSL5, FBXO32 and KLF9), as well as the expression of nuclear T3 receptor THRB. T3 treatment reversed the gene expression changesinduced by hypothyroid serum, confirming that the observed effects resulted from decreased T3 concentrations in the patients' sera.

Conclusions: A hypothyroid milieu alters the transcriptomic profile of premalignant breast cells, increasing the expression of T3‑responsive oncogenes and decreasing the expression of T3‑regulated tumor suppressors. Further studies are required to determine whether these changes promote or attenuate malignant progression.