Differential expression patterns and clinical significance of estrogen receptor-α and β in papillary thyroid carcinoma

Abstract

BackgroundThe incidence of papillary thyroid cancer (PTC) is markedly higher in women than men during the reproductive years. In vitro studies have suggested that estrogen may play an important role in the development and progression of PTC through estrogen receptors (ERs). This study aimed to investigate the expression patterns of the two main ER subtypes, α and β1 (wild-type ERβ), in PTC tissue and their clinical significance.MethodsImmunohistochemical staining of thyroid tissue sections was performed to detect ER expression in female patients with PTC (n = 89) and nodular thyroid goiter (NTG; n = 30) using the Elivision™ plus two-step system. The relationships between ER subtype expression and clinicopathological/biological factors were further analyzed.ResultsThe positive percentage and expression levels of ERα were significantly higher in female PTC patients of reproductive age (18–45 years old; n = 50) than age-matched female NTG patients (n = 30), while ERβ1 exhibited the opposite pattern. There was no difference in ERα or ERβ1 expression between female PTC patients of reproductive age and those of advanced reproductive age (>45 years old; n = 39). In the female PTC patients of reproductive age, ERα expression level was positively correlated with that of Ki-67, while ERβ1 was negatively correlated with mutant P53. Furthermore, more patients with exclusively nuclear ERα expression had extrathyroidal extension (ETE) as compared with those with extranuclear ERα localization. VEGF expression was significantly decreased in female PTC patients of reproductive age with only nuclear ERβ1 expression when compared with those with extranuclear ERβ1 localization. In PTC patients of advanced reproductive age, neither ERα nor ERβ1 expression showed any correlation with that of Ki-67, mutant P53, VEGF, tumor size, TNM stage, ETE, or lymph node metastases.ConclusionsThe differential expression patterns of the two ER subtypes between PTC and NTG indicate that ERα may be a useful immunohistochemical marker for differential diagnosis of PTC. The associations of ER subtype expression with Ki-67, mutant P53, VEGF expression and ETE in female PTC patients of reproductive age suggest that estrogen-activated ERα may mediate stimulatory effects on PTC growth and progression whereas ERβ1 has some inhibitory actions.

Expression of the estrogen receptor α, progesterone receptor and epidermal growth factor receptor in papillary thyroid carcinoma tissues

“…These isoforms are coded for by distinct genes and are expressed differently in human tissues during morphogenesis and in adult life (21,22). The expression pattern of ER isoforms has been demonstrated in neoplastic and non-cancerous human thyroid tissues; however, the results are not consistent (19,20). Experimental studies have revealed that estrogen affects PTC development by interacting with ER at the level of target thyroid cells, thereby promoting the proliferation of mutated follicular cells (23).…”

“…There are an increasing number of studies indicating that estrogen may exert a direct effect on tumorigenesis in human thyroid cells by ER-dependent or ER-independent mechanisms, through modulating cell proliferation and regulating the function of the thyroid (8,19,20). The mechanistic evidence for these effects on thyroid function and growth regulation was reviewed by Santin and Furlanetto (8).…”

Estrogen and its role in thyroid cancer

“…Silencing with selective siRNAs of either ERa or ERb showed contrary effects and thus confirmed the stimulation experiments. Very recently, a study of 89 females with PTC, which correlated ER expression with tumor size and proliferation marker Ki-67, reaffirmed the role of ERa in growth stimulation of these tumors and, on the other hand, an inhibitory effect of ERb (Huang et al 2014). …”

Thyroid Cancer in the Pediatric Age in Sicily: Influence of the Volcanic Environment

“…As already reported, gender is an age-specific effect modifier for thyroid cancer incidence (29), explained by the different sex hormone pattern between females and male in the prepubertal and postpubertal ages. Estrogen receptors (ER) are present in normal and neoplastic thyroid tissue and estrogen-activated ERα may represent a stimulatory effect for PTC growth and progression (30)(31)(32).…”