title: Tamoxifen-associated malignant endometrial tumors: pathologic features and expression of hormone receptors estrogen-alpha, estrogen-beta and progesterone; a case controlled study.
abstract: OBJECTIVE
  Expression analysis of estrogen receptor-beta (ER-beta) and estrogen receptor-alpha (ER-alpha) in tamoxifen-associated malignant endometrial tumors (TAMET) has not previously been published. Antiestrogens complexed with ER-beta have been reported to result in activation of the activator protein-1 (AP-1) pathway that may result in cell proliferation and tumor growth. In this study, the pathologic features and expression of ER-alpha, ER-beta and progesterone receptor (PR) in TAMET were determined and compared to matched cases of non-tamoxifen-associated endometrial cancers.
  
  
  METHODS
  TAMET (n = 33) were evaluated for pathologic features (tumor type, grade, depth of myometrial invasion, lymphvascular space invasion and lymph node status), expression of ER-alpha, ER-beta and PR, and survival data (mean follow-up: 28.7 months). Each case was matched to two control patients with spontaneous endometrial cancers according to tumor type, grade and stage as well as patient age and weight (mean follow-up: 51.5 months). Formalin-fixed paraffin-embedded tissue sections were immunostained with anti-ER-alpha (1D5, Dako, Carpinteria, CA) and anti-PR (PgR636, Dako). Expression scores were determined as a sum of the product of staining intensity and proportion of cells staining (H-score). Deparaffinized sections of tumor were microdissected followed by RNA isolation. Quantification of ER-beta mRNA was performed by real-time quantitative RT-PCR with results expressed as a percentage of beta-actin mRNA.
  
  
  RESULTS
  Of the 33 cases 20 were endometrioid (8 grade 1, 10 grade 2, 2 grade 3), 9 papillary serous and 4 malignant mullerian mixed tumors. Using a multivariate conditional regression model, TAMET had lower ER-alpha expression (P = 0.018), higher PR expression (P = 0.029), and more frequent expression of ER-beta (P = 0.032) as compared to control cases. Cases with TAMET had more deaths from cancer and significantly worse survival from disease than controls (P = 0.01 by a log rank test).
  
  
  CONCLUSIONS
  TAMET are characterized by a lower expression of ER-alpha, higher expression of PR and more frequent expression of ER-beta as compared to spontaneous tumors. Differential expression of ER-alpha and ER-beta may alter the expression of key target genes (such as those induced by AP-1-dependent gene transcription), and contribute to the pathogenesis and clinical behavior of these tumors. Survival from disease was significantly worse for cases with TAMET as compared to controls.
authors.affiliation: Division of Gynecologic Oncology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Wilder
authors.forename: Shahin
authors.initials: S
authors.lastname: Shajahan
authors.forename: Nada H
authors.initials: NH
authors.lastname: Khattar
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Wilder
authors.forename: Jianming
authors.initials: J
authors.lastname: Yin
authors.forename: Rodney S
authors.initials: RS
authors.lastname: Rushing
authors.forename: Rick
authors.initials: R
authors.lastname: Beaven
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kaetzel
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Ueland
authors.forename: John R
authors.initials: JR
authors.lastname: van Nagell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kryscio
authors.forename: Subodh M
authors.initials: SM
authors.lastname: Lele
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D016022:Case-Control Studies; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D006801:Humans; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D013629:Tamoxifen / Q000009:adverse effects*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen