Iuri Martin Goemann
DECREASED EXPRESSION OF THE TYPE 3 DEIODINASE RELATES TO LOWER SURVIVAL IN BREAST CANCER
Iuri M. Goemann1, Vicente R. Marczyk1, Mariana Recamonde-Mendoza2,3, Simone M. Wajner1, Marcia S. Graudenz4,Ana Luiza Maia1
Introduction: Breast cancer is a heterogeneous disease and the identification of biomarkers that predict tumor behavior is warranted in improving patient survival. Thyroid hormones (THs) are critical regulators of cellular processes and changes on TH levels impact on all the hallmarks of cancer. Disturbed expression of type 3 deiodinase (DIO3), the main TH-inactivating enzyme, has been demonstrated in human neoplasias. Objectives: To evaluate DIO3 expression and prognostic significance in breast cancer. Methods: DIO3 expression was evaluated by immunohistochemistry in a primary cohort of 53 samples of breast tissue and validated in a second cohort using the RNA-Seq data from the TCGA database. Clinicopathological data were retrieved from both populations. DNA methylation and clinical data for 890 samples from the TCGA-BRCA study were also obtained. Results: DIO3 expression was present in normal and tumoral breast glandular tissue. DIO3 mRNA expression was reduced in tumor samples when compared to normal tissue (logFC = -1.54, p < 0.0001). Unexpectedly, loss of DIO3 expression was associated with increased mortality (HR 4.29; 95% CI 1.24-14.7) in the primary cohort. Accordingly, in the validation cohort, low DIO3 mRNA expression was associated with an increased risk for death in a multivariate model [HR 1.55 (95% CI, 1.07-2.24); p = 0.02]. DNA methylation analysis revealed that DIO3 gene promoter is hypermethylated in tumors when compared to normal tissue (p < 0.0001). Conclusion: DIO3 is expressed in normal and tumoral breast tissue. Decreased DIO3 expression is a prognostic marker of poor overall survival in breast cancer patients. Loss of DIO3 expression is associated with gene promoter hypermethylation and might have therapeutic implications. Conflict of interest: None declared.