title: Evidence of a functional estrogen receptor in parathyroid adenomas.
abstract: BACKGROUND
  Primary hyperparathyroidism (PHPT) is most frequently present in postmenopausal women. Although the involvement of estrogen has been suggested, current literature indicates that parathyroid tumors are estrogen receptor (ER) α negative.
  
  
  OBJECTIVE
  The aim of the study was to evaluate the expression of ERs and their putative function in parathyroid tumors.
  
  
  METHODS
  A panel of 37 parathyroid tumors was analyzed for expression and promoter methylation of the ESR1 and ESR2 genes as well as expression of the ERα and ERβ1/ERβ2 proteins. Transcriptome changes in primary cultures of parathyroid adenoma cells after treatment with the selective ERβ1 agonist diarylpropionitrile (DPN) and 4-hydroxytamoxifen were identified using next-generation RNA sequencing.
  
  
  RESULTS
  Immunohistochemistry revealed very low expression of ERα, whereas all informative tumors expressed ERβ1 (n = 35) and ERβ2 (n = 34). Decreased nuclear staining intensity and mosaic pattern of positive and negative nuclei of ERβ1 were significantly associated with larger tumor size. Tumor ESR2 levels were significantly higher in female vs. male cases. In cultured cells, significantly increased numbers of genes with modified expression were detected after 48 h, compared to 24-h treatments with DPN or 4-hydroxytamoxifen, including the parathyroid-related genes CASR, VDR, JUN, CALR, and ORAI2. Bioinformatic analysis of transcriptome changes after DPN treatment revealed significant enrichment in gene sets coupled to ER activation, and a highly significant similarity to tumor cells undergoing apoptosis.
  
  
  CONCLUSIONS
  Parathyroid tumors express ERβ1 and ERβ2. Transcriptional changes after ERβ1 activation and correlation to clinical features point to a role of estrogen signaling in parathyroid function and disease.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska University Hospital, Cancer Centrum Karolinska, R8:04, SE-171 76 Stockholm, Sweden. Felix.Haglund@ki.se
authors.forename: Felix
authors.initials: F
authors.lastname: Haglund
authors.forename: Ran
authors.initials: R
authors.lastname: Ma
authors.forename: Mikael
authors.initials: M
authors.lastname: Huss
authors.forename: Luqman
authors.initials: L
authors.lastname: Sulaiman
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Inga-Lena
authors.initials: IL
authors.lastname: Nilsson
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.forename: Johan
authors.initials: J
authors.lastname: Hartman
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059467:Transcriptome
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen