Expression and role of estrogen receptor alpha and beta in medullary thyroid carcinoma: different roles in cancer growth and apoptosis.
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.
Cho
Mi Ae
MA
Division of Endocrinology, Yonsei University College of Medicine, Seoul, South Korea.
Lee
Mi Kyung
MK
Nam
Kee-Hyun
KH
Chung
Woung Youn
WY
Park
Cheong Soo
CS
Lee
Ju Hyeong
JH
Noh
Taewoong
T
Yang
Woo Ick
WI
Rhee
Yumie
Y
Lim
Sung-Kil
SK
Lee
Hyun Chul
HC
Lee
Eun Jig
EJ
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
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