Expression and role of estrogen receptor α and β in medullary thyroid carcinoma:: different roles in cancer growth and apoptosis

Meduflary thyroid carcinoma (MTC) originates front parafollicular C cells. Estrogen receptor beta (ER beta) expression was detected in normal parafollicular C cells and MTC tumor tissue, but ER alpha expression in MTC tumors still remains undetermined. The appearance and loss ofER alpha or ER beta expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ER alpha, ER beta, and Ki67, a mitotic index, in 11 human MTC tissue samples. ER alpha was detected in 10 cases (91%), and ER beta expression was observed in 8 cases (72.7%). A majority (8/10) of ER alpha-positive tumors showing ER beta Ki67 expression was detected in three cases (27.3%). Neither clinical parameters nor tumor node metastasis (TNM) tumor staging was correlated with the positivity for ERs or Ki67. To investigate the biological role of each ER, we used ER-negative MTC TT cells and adenoviral vectors carrying ER alpha (Ad-ER alpha), ER beta (Ad-ER beta), estrogen response element (ER-E)-Luc (Ad-ERE-Luc), and activator protein 1 (AP1)-Luc (Ad-AP1-Luc). Estrogen stimulated and anti-estrogen, ICI 1,82 780, suppressed ERE reporter activity in TT cells expressing ER alpha or ER beta, suggesting that both ERs use the same classical ER-E-mediated pathway. Ad-ER alpha infection stimulated TT cell growth; in contrast, Ad-ER infection suppressed their growth. Apoptosis was detected in Ad-ER beta-infected TT cells. Estrogen and antiestrogen suppressed AP1 activity in Ad-ER alpha-infected cells, whereas upon Ad-ER beta infection estrogen further stimulated AP1 activity which in turn is suppressed by anti-estrogen, suggesting that each ER acts differently through a non-ERE-mediated pathway. Our results suggest that ER alpha and ER beta may play different roles in MTC tumor growth and progession.