Decreased expression of the thyroid hormone-inactivating enzyme type 3 deiodinase is associated with lower survival rates in breast cancer

Abstract

Thyroid hormones (THs) are critical regulators of cellular processes, while changes in their levels impact all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH-inactivating enzyme, occurs in several human neoplasms and has been associated with adverse outcomes. Here, we investigated the patterns of DIO3 expression and its prognostic significance in breast cancer. DIO3 expression was evaluated by immunohistochemistry in a primary cohort of patients with breast cancer and validated in a second cohort using RNA sequencing data from the TCGA database. DNA methylation data were obtained from the same database. DIO3 expression was present in normal and tumoral breast tissue. Low levels of DIO3 expression were associated with increased mortality in the primary cohort. Accordingly, low DIO3 mRNA levels were associated with an increased risk of death in a multivariate model in the validation cohort. DNA methylation analysis revealed that the DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue. In conclusion, DIO3 is expressed in normal and tumoral breast tissue, while decreased expression relates to poor overall survival in breast cancer patients. Finally, loss of DIO3 expression is associated with hypermethylation of the gene promoter and might have therapeutic implications.

The TSH/Thyroid Hormones Axis and Breast Cancer

“…There was no difference in DIO3 expression between cancers with positive or negative ER and positive or negative HER2 receptors. Patients with higher DIO3 levels (above the median expression by immunohistochemistry) had a better survival than patients with DIO3 expression below the median of the group [74]. A similar difference in survival was observed when breast cancer patients from the TCGA cohort were categorized according to their DIO3 mRNA expression levels.…”

“…The deiodinases (DIOs) are an integral part of the TSH/thyroid hormone axis and can regulate the actions of the axis through the production and disposition of thyroid hormones. DIO3 is expressed in the normal mammary luminal duct and acini cells and, at similar levels, in breast carcinomas [74]. There was no difference in DIO3 expression between cancers with positive or negative ER and positive or negative HER2 receptors.…”

Breast Cancer in Previously Thyroidectomized Patients: Which Thyroid Disorders are a Risk factor?

“…However, the researchers stressed the lack of data regarding treatments and other confounders. These findings have an intriguing confirmation in the observation that reduced expression of type 3 deiodinase (a powerful peripheral inactivator of thyroid hormone) is associated with poor survival [ 22 ].…”

Deiodinases and Cancer

“…In other words, could the deiodinase profile serve as a marker of tumor staging/grading? This is still an open issue, although the correlations arising from the analysis of large in silico data sets between D2 expression and poor prognosis in skin cancer and reduced D3 expression and lower survival rates in breast cancer support this possibility ( 93 ).…”