Relationship between expression of coactivators and corepressors of hormone receptors and resistance of ovarian cancers to growth regulation by steroid hormones

OBJECTIVE: To determine whether aberrant expression of hormone receptor cor epressors or coactivators or defects in estrogen receptor-mediated transcri ption 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 re ceptor (PR), the nuclear receptor corepressors N-CoR and SMRT, and the ster oid receptor coactivator BRG-1 in ovarian cancer cell liens and primary can cers. The effect of BRG-1 transfection on ER-mediated transcription was exa mined. We also determined the effect of estrogen and the pure estrogen anta gonist ICI 182,780 on cell cycle profile and expression of ER. Finally, we examined the ability of estrogen to upregulated expression of known estroge n-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 expres sion of corepressors and hormone receptor status. All of the primary ovaria n cancers and cell lines expressed BRG-1. Estrogen stimulation of two cell lines expressing ER (SKOV3, OVCA 432) elicited low levels of ER-mediated tr anscription that was not enhanced by BRG-1 transfection. ICI 182,780 did no t induce cell cycle arrest in these cell lines, but there was evidence of d ownregulation of ER, indicating a ligand-receptor interaction. However, est rogen 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 c ancers to hormonal therapy. Further studies are needed to elucidate the mec hanisms underlying the inability of ovarian cancers to undergo ER-mediated transcription if we hope to understand their resistance to hormonal therapy . Copyright (C) 2001 by the Society of Gynecologic Investigation.