Thyroid hormone receptor α in breast cancer: prognostic and therapeutic implications

Abstract

We determined the expression of two transcriptional variants of thyroid hormone receptor alpha (THRα1 and THRα2) in samples from a cohort of breast cancer patients and correlated expression levels with survival. 130 women who were diagnosed with invasive breast carcinoma between 2007 and 2008 were included. Representative sections of their tumours were analyzed in triplicate on a tissue microarray for expression of THRα1 and THRα2 by immunohistochemistry. The prognostic significance of THRα1 and THRα2 expression was assessed using Kaplan-Meier survival analyses, adjusted for known prognostic factors. Seventy-four percent of tumours had high expression of THRα1 (Allred score ≥6) and 40 % had high expression of THRα2. Expression of THRα2 correlated positively with ER expression (p < 0.001) and with PR expression (p < 0.001), but negatively with HER2 expression (p = 0.018). Patients with low THRα2 expression had inferior 5-year overall survival (75.3 %) compared to those with high expression (91.7 %; p = 0.06). In a multivariate model, high THRα2 expression was a significant and independent prognosticator of improved overall survival (HR = 0.84; 95 % CI 0.71-0.98). Many breast tumours express THRα2 at high levels and these patients experience improved survival. Thyroid hormone signalling may be important in a proportion of breast cancers and THRα2 expression may be a regulator of signalling in this pathway.

Cytoplasmic and Nuclear Forms of Thyroid Hormone Receptor β1 Are Inversely Associated with Survival in Primary Breast Cancer

“…Previously, we had demonstrated that nuclear THRα2 expression tends to be an independent and favorable prognostic marker for survival in a small cohort of 82 invasive BC cases [39]. This was confirmed in another cohort of 130 invasive BC samples, where THRα2 (nuclear and cytoplasmic) negatively correlated with HER2 status, and positively with ER/PR and favorable OS [40]. In the present work, we confirmed that nuclear THRα2 was significantly correlated with a favorable prognosis.…”

Overexpression of <em>HDAC9</em> is associated with poor prognosis and tumor progression of breast cancer in Chinese females

“… 22 Jerzak et al reported that the thyroid hormone receptor α ( THRα ) represented an efficient prognostic biomarker in breast cancer patients. 23 All these data indicated the pivotal role of cancer-related molecules for breast cancer prognosis. Consequently, more molecular biomarkers should be identified for prediction of prognosis in breast cancer.…”

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer

“…In BRCA‐positive breast cancer TRα and TRβ exhibit opposing roles in prognostic survival; greater expression of TRα strongly correlates with a decrease in overall survival whereas expression of TRβ is associated with improved survival . Additionally, the isoform of TRα has been observed to be critical as expression of TRα2, a splice variant without a triiodothyronine (T 3 ) binding site, is associated with improved survival . TRα2 acts antagonistically to TRα1, which exhibits a functional LBD, by binding to TREs and blocking TRα1 from interacting with the chromatin.…”