Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro.

Wilson, Sean T.; Blask, David E.; Lemus-Wilson, Athena

doi:10.1210/jcem.75.2.1639964

Cited by 32 publications

(30 citation statements)

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“…Several studies have demonstrated the antiproliferative role of melatonin using an MCF7 cell model to study the anti-estrogenic effect of this hormone (Hill and Blask, 1988;Wilson et al, 1992;Molis et al, 1994Molis et al, , 1995Lissoni et al, 1995). Estradiol was used in the present study to induce MCN increase in the testis to verify the effect(s) of melatonin on mast cell accumulation.…”

Section: Discussionmentioning

confidence: 92%

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Inhibition of the increased 17β-estradiol-induced mast cell number by melatonin in the testis of the frog Rana esculenta, in vivo and in vitro

Izzo

d’Istria

Serino

et al. 2004

Journal of Experimental Biology

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Section: Discussionmentioning

confidence: 92%

“…In addition, melatonin acts as an antiestrogen (Molis et al, 1994) since it inhibits the expression of estrogen-regulated genes (Molis et al, 1995), potentiates the sensitivity of MCF7 to tamoxifen (Wilson et al, 1992) and modulates the transcription of estrogen receptor in this cell line.…”

mentioning

confidence: 99%

Inhibition of the increased 17β-estradiol-induced mast cell number by melatonin in the testis of the frog Rana esculenta, in vivo and in vitro

Izzo

d’Istria

Serino

et al. 2004

Journal of Experimental Biology

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“…One of the proposed properties of melatonin is its role as an oncostatic agent on hormone-dependent tumors. It has also been described that melatonin exerts antiproliferative effects on MCF7 cells, which has become a useful model to study the antiestrogenic effect of the pineal hormone (11,(32)(33)(34)(35). In synchronized MCF7 cells, both estrogen-dependent transcription and proliferation are inhibited by co-treatment with melatonin.…”

Section: Discussionmentioning

confidence: 99%

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

Río¹,

García-Pedrero²,

Martínez‐Campa³

et al. 2004

Journal of Biological Chemistry

129

102

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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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“…The data which uphold this hypothesis are: (a) melatonin inhibits proliferation only in those cells expressing ERα (Cos & Sánchez-Barceló 2000a), (b) melatonin blocks the mitogenic effects of estradiol as well as counteracts the estradiol-induced invasiveness of MCF-7 cells (Cos et al 1998), (c) melatonin potentiates the sensitivity of MCF-7 cells to antiestrogens such as tamoxifen (Wilson et al 1992) or MDA-MB-231 cells (ERα negative) significantly enhances the growth-suppression effects of melatonin only in MCF-7 cells, that is to say, in those also expressing ER , and (e) melatonin inhibits the expression of estrogen-regulated genes such as pS2 or cathepsine (Molis et al 1995).…”

Section: Mechanisms Involved In the Effects Of Melatonin On Mcf-7 Cellsmentioning

confidence: 99%

Melatonin and mammary cancer: a short review.

Sánchez‐Barceló¹,

Cos²,

Fernandez³

et al. 2003

Endocrine-Related Cancer

141

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Melatonin is an indolic hormone produced mainly by the pineal gland. The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, as a naturally occurring antiestrogen, thereby influencing their proliferative rate. The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor (ER)-positive breast tumors. However, later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type. These studies described 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. Since light inhibits melatonin secretion, the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis. From in vivo studies on animal models of chemically induced mammary tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors, while pinealectomy usually has the opposite effects. Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice (c-neu and N-ras) and mice from strains with a high tumoral incidence.In vitro experiments, carried out with the ER-positive MCF-7 human breast cancer cells, demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol: (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastasic 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 the cell surface adhesion proteins E-cadherin and β 1 -integrin.The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway. In this sense it has been demonstrated that melatonin down-regulates the expression of ERα and inhibits the binding of the estradiol-ER complex to the estrogen response element (ERE) in the DNA. The characteristics of melatonin's oncostatic actions, comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished, give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer.

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Melatonin augments the sensitivity of MCF-7 human breast cancer cells to tamoxifen in vitro.

Cited by 32 publications

References 5 publications

Inhibition of the increased 17β-estradiol-induced mast cell number by melatonin in the testis of the frog Rana esculenta, in vivo and in vitro

Inhibition of the increased 17β-estradiol-induced mast cell number by melatonin in the testis of the frog Rana esculenta, in vivo and in vitro

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

Melatonin and mammary cancer: a short review.

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