The contributions of oestrogen receptor isoforms to the development of papillary and anaplastic thyroid carcinomas.
Oestrogen (E2) is known to promote the proliferation of thyroid papillary carcinoma cells (KAT5). However, the molecular mechanism responsible is not well understood. In the study reported herein, the localization of ER alpha (ERalpha) and beta (ERbeta) in KAT5 and anaplastic carcinoma cells (FRO) was studied by immunofluorescence staining and by immunoblotting the proteins in subcellular fractions. Cell proliferation and apoptosis were also determined together with the expression of relevant proteins. The pattern of the subcellular localization of ERalpha and ERbeta differed between papillary and anaplastic cancer. Upon E2 treatment, the level of ERalpha increased in the nuclei of papillary cancer cells but ERbeta remained unchanged. The level of mitochondrial ERbeta surpassed that of ERalpha in anaplastic cancer cells. The different locations of ERalpha and ERbeta in KAT5 and FRO agreed with the finding that E2 promoted the proliferation of KAT5 but inhibited or did not affect that of FRO cells, and with the proposed functions of these two receptors. E2 inhibited the level of Bax in the mitochondria of papillary cancer, followed by a decrease of cytochrome c and/or apoptosis-inducing factor (AIF) release from the mitochondria into the cytosol. However, in anaplastic cancer, E2 promoted the expression of Bax in the mitochondria and the release of cytochrome c and/or AIF from mitochondria into the cytosol. Our results may explain the differences in epidemiology and responses to anti-tumour therapy between papillary and anaplastic cancer in terms of the subcellular localization of ER isoforms. In conclusion, the findings provide evidence to support the observation that E2 is an important factor in the development of thyroid cancer. The subcellular localization of ERalpha and ERbeta may account for the different pathogenesis of thyroid papillary and anaplastic cancers.
Zeng
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Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
Chen
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Vlantis
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van Hasselt
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D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology; D047629:Estrogen Receptor beta / Q000378:metabolism / Q000502:physiology; D004967:Estrogens / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism* / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D051028:bcl-2-Associated X Protein; D000077267:Fulvestrant; D004958:Estradiol; D045304:Cytochromes c