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An interaction between cellular estrogen response and melatonin signaling mediated by G-protein coupled receptors is present in breast cancer cells. In this study, the effect of antiestrogens on basal and melatonin-modulated expression of MT1 melatonin receptor in breast and ovarian cancer cells was examined. For this purpose, the effects of the selective estrogen receptor modulator tamoxifen and pure antiestrogen ICI 182,780 on MT1 expression in estrogen receptor (ER) ·-positive and -negative breast and ovarian cancer cell lines cultured in medium supplemented with 1 nM 17-ß estradiol were assessed by Western blot analysis. We were able to detect expression of the MT1 receptor in SK-OV-3 and OVCAR-3 cells and report its up-regulation by melatonin in both ovarian cancer cell lines. MT1 expression was observed to be significantly weaker in ER·-positive MCF-7 and OVCAR-3 cells than in ER·-negative MDA-MB-231 and SK-OV-3 cells. Treatment with the pure antiestrogen ICI 182,780 increased MT1 receptor expression in OVCAR-3 ovarian cancer cells, but decreased MT1 expression in MCF-7 breast cancer cells. No effect of ICI 182,780 on MT1 expression was observed in the ER·-negative cell lines SK-OV-3 and MDA-MB-231. After treatment with 4-OH tamoxifen, down-regulation of basal MT1 receptor expression in ER·-positive MCF-7 cells and inhibition of melatonininduced up-regulation of MT1 in OVCAR-3 ovarian cancer cells were observed. In contrast, treatment with 4-OH tamoxifen increased the MT1 receptor level in ER·-negative SK-OV-3 ovarian cancer cells. Our findings support the existence of close interaction between estrogen and melatonin signaling. Moreover, our data suggest that melatonin signaling is modulated by antiestrogens in breast and ovarian cancer cells. Introduction The pineal hormone melatonin affects cancer cells in various ways (1). In vitro experiments carried out with estrogen receptor (ER)-positive MCF-7 human breast cancer cells demonstrated that melatonin modulates the length of the cell cycle, increases expression of p53 and p21WAF1 proteins (2), reduces metastatic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness. This effect is mediated, at least in part, by a melatonin-induced increase in the expression of cell surface adhesion proteins E-cadherin and ß1-integrin (3). Furthermore, treatment with melatonin reduces the incidence of spontaneous mammary tumors in different strains of transgenic mice (c-neu and N-ras) and strains with a high tumor incidence (4,5). The direct oncostatic effect of melatonin depends on its interaction with the cellular estrogen response. Melatonin impairs estrogen receptor signaling in breast cancer cells both by down-regulation of ER· expression and inhibition of ER-binding to DNA (6,7). Melatonin was demonstrated to be a specific inhibitor of estradiol-induced, ER·-mediated transcription and its mitogenic effects in both estrogen response elementand AP1-regulated promoters, whereas ERß-mediated transactivation was not inhibited or even activated at certain promoters. It has been demonstrated that the sensitivity of MCF-7 cells to melatonin depends on a high ER·/ERß ratio, and overexpression of ERß results in MCF-7 cells becoming insensitive to this hormone (8). Different experimental studies suggest that estradiol stimuli modulate the cellular response to melatonin and regulate expression of melatonin receptors. Melatonin actions are mediated both by high affinity membrane receptors and nuclear receptors (9). MT1 membrane melatonin receptor belongs to the super-family of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors. It was previously demonstrated that MT1 receptor expression in the rat ovary is down-regulated after estrogen exposure (10). In this study, we examined the effect of substances acting as inhibitors of estrogen receptor signaling on MT1 receptor expression in breast and ovarian cancer cells. Given that selective estrogen receptor modulators (SERMs) such as tamoxifen and pure antiestrogens like ICI 182,780 are important treatment options in hormone-dependent gynecological cancer, and antiestrogens are appropriate tools to further analyze the interaction between estrogen and ONCOLOGY REPORTS 15: 231-235, 2006 231 Antiestrogens modulate MT1 melatonin receptor expression in breast and ovarian cancer cell lines OLIVER TREECK1*, CHANDANA HALDAR2* and OLAF ORTMANN1 1Department of Obstetrics and Gynecology, University of Regensburg, Caritas Hospital St. Josef, Regensburg, Germany; 2Pineal Research Laboratory, Department of Zoology, Banaras Hindu University, Varanasi-5, India Received June 27, 2005; Accepted August 16, 2005 _________________________________________ Correspondence to: Dr Oliver Treeck, Department of Obstetrics and Gynecology, University Regensburg, Caritas Krankenhaus St. Josef, Landshuter Str. 65, 93053 Regensburg, Germany E-mail: [email protected] *Contributed equally