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¹ Division of Endocrinology,
² Thyroid Cancer Clinic and
³ Research Institute of Endocrinology, Yonsei University College of Medicine, Seoul, South Korea
⁴ Department of Pathology, National Health Insurance Corporation, Ilsan Hospital, Koyang, South Korea
⁵ Department of Surgery,
⁶ Department of Pathology and
⁷ Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul, South Korea
⁸ Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA

(Correspondence should be addressed to E J Lee at Division of Endocrinology, Yonsei University College of Medicine, 262 Seongsanno Seodaemungu, Seoul 120-752, South Korea; Email: ejlee423{at}yuhs.ac)

Medullary thyroid carcinoma (MTC) originates from parafollicular C cells. Estrogen receptor ß(ERß) expressionwas detected in normal parafollicular C cells and MTC tumor tissue, but ER expression in MTC tumors still remains undetermined. The appearance and loss of ER or ERß expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ER, ERß, and Ki67, a mitotic index, in 11 human MTC tissue samples. ER was detected in 10 cases (91%), and ERß expression was observed in 8 cases (72.7%). A majority (8/10) of ER-positive tumors showing ERß 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 (Ad-ER), ERß (Ad-ERß), estrogen response element (ERE)-Luc (Ad-ERE-Luc), and activator protein 1 (AP1)-Luc (Ad-AP1-Luc). Estrogen stimulated and anti-estrogen, ICI 182 780, suppressed ERE reporter activity in TT cells expressing ER or ERß, suggesting that both ERs use the same classical ERE-mediated pathway. Ad-ER infection stimulated TT cell growth; in contrast, Ad-ERß infection suppressed their growth. Apoptosis was detected in Ad-ERß-infected TT cells. Estrogen and anti-estrogen suppressed AP1 activity in Ad-ER-infected cells, whereas upon Ad-ERß 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 and ERß may play different roles in MTC tumor growth and progression.