title: The role of oestrogen receptor {alpha} in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2.
abstract: Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERalpha, ERbeta, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERalpha was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERalpha and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan-Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.
authors.affiliation: School of Medicine and Medical Science, UCD Conway Institute, St Vincent's University Hospital and University College Dublin, Dublin 4, Ireland.
authors.forename: Dara O
authors.initials: DO
authors.lastname: Kavanagh
authors.forename: Marie
authors.initials: M
authors.lastname: McIlroy
authors.forename: Eddie
authors.initials: E
authors.lastname: Myers
authors.forename: Fiona
authors.initials: F
authors.lastname: Bane
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Crotty
authors.forename: E
authors.initials: E
authors.lastname: McDermott
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Hill
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056970:Co-Repressor Proteins / Q000378:metabolism / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D016019:Survival Analysis; D013964:Thyroid Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D056970:Co-Repressor Proteins; D047628:Estrogen Receptor alpha; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; C508053:ERBB2 protein, human