Tamoxifen-associated malignant endometrial tumors: Pathologic features and expression of hormone receptors estrogen-α, estrogen-β and progesterone; A case controlled study

James L. Wilder, Shahin Shajahan, Nada H. Khattar, Dawn M. Wilder, Jianming Yin, Rodney S. Rushing, Rick Beaven, Charlotte Kaetzel, Frederick R. Ueland, John R. Van Nagell, Richard J. Kryscio, Subodh M. Lele

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Objective. Expression analysis of estrogen receptor-beta (ER-β) and estrogen receptor-alpha (ER-α) in tamoxifen-associated malignant endometrial tumors (TAMET) has not previously been published. Antiestrogens complexed with ER-β 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-α, ER-β 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-α, ER-β 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-α (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-β mRNA was performed by real-time quantitative RT-PCR with results expressed as a percentage of β-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-α expression (P = 0.018), higher PR expression (P = 0.029), and more frequent expression of ER-β (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). Conclusion. TAMET are characterized by a lower expression of ER-α, higher expression of PR and more frequent expression of ER-β as compared to spontaneous tumors. Differential expression of ER-α and ER-β 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.

Original languageEnglish (US)
Pages (from-to)553-558
Number of pages6
JournalGynecologic Oncology
Volume92
Issue number2
DOIs
StatePublished - Feb 2004

Keywords

  • Estrogen-α
  • Estrogen-β
  • Progesterone
  • TAMET
  • Tamoxifen-associated malignant endometrial tumors

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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    Wilder, J. L., Shajahan, S., Khattar, N. H., Wilder, D. M., Yin, J., Rushing, R. S., Beaven, R., Kaetzel, C., Ueland, F. R., Van Nagell, J. R., Kryscio, R. J., & Lele, S. M. (2004). Tamoxifen-associated malignant endometrial tumors: Pathologic features and expression of hormone receptors estrogen-α, estrogen-β and progesterone; A case controlled study. Gynecologic Oncology, 92(2), 553-558. https://doi.org/10.1016/j.ygyno.2003.10.040