Melatonin, an Endogenous-specific Inhibitor of Estrogen Receptor α via Calmodulin

Abstract

Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E 2 ) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E 2 -induced ER␣-mediated transcription in both estrogen response element-and AP1-containing promoters, whereas ER␤-mediated transactivation is not inhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ER␣/ER␤ ratio, and ectopic expression of ER␤ results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ER␣-calmodulin (CaM) complex, thus impairing the binding of E 2 ⅐ER␣⅐CaM complex to DNA and, therefore, preventing ER␣-dependent transcription. Moreover the mutant ER␣ (K302G,K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ER␣-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ER␣, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ER␣ at different levels, representing two independent ways to control ER␣ activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.Melatonin is an indole hormone that is the major secretory product of the pineal gland. The most clearly defined actions of melatonin have been demonstrated on the reproductive system of seasonally breeding animals and on circadian rhythms and sleep. A rapidly emerging avenue of investigation is the oncostatic and anti-proliferative effects of melatonin on endocrineresponsive neoplasms, especially in those concerning the mammary gland (1). The most common conclusion in animal models of tumorigenesis is that either experimental manipulations that activate the pineal gland or the administration of melatonin reduces the incidence and development of chemically induced mammary tumors, whereas pinealectomy usually stimulates breast cancer growth (2-4). Epidemiological studies have shown a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment. Because light inhibits melatonin secretion, the increase in melatonin-circulating levels might be interpreted as proof of the protective role of this hormone on mammary carcinogenesis (5). A moderate increase in breast cancer risk among women who worked extended periods of rotating night shifts (light exposure during night suppresses melatonin production) has also been described (6).Different mechanisms have been proposed to explain how melatonin could reduce the development of mammary tumors; they are indirect neuroendocrine mechanisms ...

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