title: Expression and role of estrogen receptor alpha and beta in medullary thyroid carcinoma: different roles in cancer growth and apoptosis.
abstract: Medullary thyroid carcinoma (MTC) originates from parafollicular C cells. Estrogen receptor beta(ERbeta) expressionwas detected in normal parafollicular C cells and MTC tumor tissue, but ERalpha expression in MTC tumors still remains undetermined. The appearance and loss of ERalpha or ERbeta expression has been known to play a role in the development and progression of many human cancers. We performed immunohistochemical studies of ERalpha, ERbeta, and Ki67, a mitotic index, in 11 human MTC tissue samples. ERalpha was detected in 10 cases (91%), and ERbeta expression was observed in 8 cases (72.7%). A majority (8/10) of ERalpha-positive tumors showing ERbeta 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 ERalpha (Ad-ERalpha), ERbeta (Ad-ERbeta), 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 ERalpha or ERbeta, suggesting that both ERs use the same classical ERE-mediated pathway. Ad-ERalpha infection stimulated TT cell growth; in contrast, Ad-ERbeta infection suppressed their growth. Apoptosis was detected in Ad-ERbeta-infected TT cells. Estrogen and anti-estrogen suppressed AP1 activity in Ad-ERalpha-infected cells, whereas upon Ad-ERbeta 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 ERalpha and ERbeta may play different roles in MTC tumor growth and progression.
authors.affiliation: Division of Endocrinology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Cho
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Nam
authors.forename: Woung Youn
authors.initials: WY
authors.lastname: Chung
authors.forename: Cheong Soo
authors.initials: CS
authors.lastname: Park
authors.forename: Ju Hyeong
authors.initials: JH
authors.lastname: Lee
authors.forename: Taewoong
authors.initials: T
authors.lastname: Noh
authors.forename: Woo Ick
authors.initials: WI
authors.lastname: Yang
authors.forename: Yumie
authors.initials: Y
authors.lastname: Rhee
authors.forename: Sung-Kil
authors.initials: SK
authors.lastname: Lim
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D018276:Carcinoma, Medullary / Q000378:metabolism / Q000503:physiopathology*; D002455:Cell Division; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D000077267:Fulvestrant; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D019394:Ki-67 Antigen; D018808:Transcription Factor AP-1; D000077267:Fulvestrant; D004958:Estradiol