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Relationship Between Expression of Coactivators and Corepressors of Hormone Receptors and Resistance of Ovarian Cancers to Growth Regulation by Steroid Hormones

Connette P. McMahon, MD

Edward K. Lobenhofer, PhD

Regina Whitaker, BS

Jeffrey R. Marks, PhD

Departments of Obstetrics and Gynecology, Pathology, and Surgery, Duke Umnversity Medical Center, Durham, North Carolina

Andrew Berchuck, MD

Departments of Obstetrics and Gynecology, Pathology, and Surgery, Duke Umnversity Medical Center, Durham, North Carolina; Duke University Medical Center, Division of Gynecologic Oncology, Box 3079, Durham, NC 27710

OBJECTIVE: To determine whether aberrant expression of hormone receptor corepressors or coactivators or defects in estrogen receptor—mediated transcription might underlie resistance of ovarian cancers to hormonal therapy.

METHODS: Northern analysis, Western analysis, and polymerase chain reaction were used to examine expression of estrogen receptor (ER), progesterone receptor (PR), the nuclear receptor corepressors N-CoR and SMRT, and the steroid receptor coactivator BRG-1 in ovarian cancer cell lines and primary cancers. The effect of BRG-1 transfection on ER-mediated transcription was examined. We also determined the effect of estrogen and the pure estrogen antagonist ICI 182, 780 on cell cycle profile and expression of ER. Finally, we examined the ability of estrogen to upregulate expression of known estrogen-responsive genes.

RESULTS: Among primary ovarian cancers, 18 of 52 (35%) expressed N-CoR, and 37 of 52 (71%) expressed SMRT, but there was no correlation between expression of corepressors and hormone receptor status. All of the primary ovarian cancers and cell lines expressed BRG-1. Estrogen stimulation of two cell lines expressing ER (SKOV3, OVCA 432) elicited low levels of ER-mediated transcription that was not enhanced by BRG-1 transfection. ICI 182, 780 did not induce cell cycle arrest in these cell lines, but there was evidence of downregulation of ER, indicating a ligand-receptor interaction. However, estrogen did not elicit increased transcription of estrogen-responsive genes (PR, myc, fos, pS2).

CONCLUSION: Inappropriate expression of the nuclear corepressors N-CoR and SMRT or the coactivator BRG-1 does not underlie the resistance of ovarian cancers to hormonal therapy. Further studies are needed to elucidate the mechanisms underlying the inability of ovarian cancers to undergo ER-mediated transcription if we hope to understand their resistance to hormonal therapy.

Key Words: Ovarian cancer • N-CoR • SMRT • estrogen receptor

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