Melatonin inhibits both ERα activation and breast cancer cell proliferation induced by a metalloestrogen, cadmium

Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, Santander, Spain.
Journal of Pineal Research (Impact Factor: 9.6). 06/2006; 40(4):291-6. DOI: 10.1111/j.1600-079X.2006.00315.x
Source: PubMed


Cadmium (Cd) is a heavy metal affecting human health both through environmental and occupational exposure. There is evidence that Cd accumulates in several organs and is carcinogenic to humans. In vivo, Cd mimics the effect of estrogens in the uterus and mammary gland. In estrogen-responsive breast cancer cell lines, Cd stimulates proliferation and can also activate the estrogen receptor independent of estradiol. The ability of this metalloestrogen to increase gene expression in MCF7 cells is blocked by anti-estrogens suggesting that the activity of these compounds is mediated by ER alpha. The aims of this work were to test whether melatonin inhibits Cd-induced proliferation in MCF7 cells, and also to study whether melatonin specifically inhibits Cd-induced ER alpha transactivation. We show that melatonin prevents the Cd-induced growth of synchronized MCF7 breast cancer cells. In transient transfection experiments, we prove that both ER alpha- and ER beta-mediated transcription are stimulated by Cd. Melatonin is a specific inhibitor of Cd-induced ER alpha-mediated transcription in both estrogen response elements (ERE)- and AP1-containing promoters, whereas ER beta-mediated transcription is not inhibited by the pineal indole. Moreover, the mutant ER alpha-(K302G, K303G), unable to bind calmodulin, is activated by Cd but becomes insensitive to melatonin treatment. These results proved that melatonin inhibits MCF7 cell growth induced by Cd and abolishes the stimulatory effect of the heavy metal in cells expressing ER alpha at both ERE-luc and AP1-luc sites. We can infer from these experiments that melatonin regulates Cd-induced transcription in both ERE- and AP1 pathways. These results also reinforce the hypothesis of the anti-estrogenic properties of melatonin as a valuable tool in breast cancer therapies.

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Available from: Samuel Cos, Nov 14, 2014
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    • "In addition, as reported by Julin et al. (2012), both in vivo and in vitro studies provide evidence that Cd may act as a metalloestrogen (Johnson et al., 2003; Safe, 2003; Brama et al., 2007; Zang et al., 2009; Garcia-Morales et al., 1994; Ali et al., 2010). Cadmium was discovered to exert estrogenic activities, such as stimulation of the proliferation of breast cancer cells (Brama et al., 2007; Martinez-Campa et al., 2006), activation and increased expression of estrogen regulated genes (Garcia-Morales et al., 1994; Liu et al., 2008) and activation of the estrogen receptor (ER)-alpha (Garcia-Morales et al., 1994; Martinez-Campa et al., 2006; Stoica et al., 2000; Wilson et al., 2004) supporting the hypothesis that this metal can potentially induce the development of hormone-dependent tumors in humans, including breast, uterus and prostate cancers (Akesson et al., 2008; Benbrahim-Tallaa et al., 2009; Bertin and Averbeck, 2006). Cd has been shown to upregulate progesterone receptor (PGR) levels in breast cancer cells, this induction being blocked by anti-estrogen (Garcia-Morales et al., 1994). "
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    ABSTRACT: Background: With tobacco smoking, diet is the main source of cadmium (Cd) exposure in the general population. The carcinogenic and estrogenic activities of Cd make it a contaminant of potential concern for hormone-dependent cancers including breast cancer. Postmenopausal women represent the most appropriate population to investigate the possible impact of exogenous factors with potential estrogenic activity on breast cancer as, after menopause, their estrogenic influence is predominant. Objectives: We systematically reviewed available studies on the association between dietary exposure to Cd and breast cancer focusing on postmenopausal women. A meta-analysis combining the risk estimators was performed and potential sources of between studies heterogeneity were traced. Methods: Studies were searched from MEDLINE through 31 January 2015 and from the reference lists of relevant publications. Six eligible studies published between 2012 and 2014 were identified and relative risk estimates were extracted. Meta-rate ratio estimates (mRR) were calculated according to fixed and random-effect models. Meta-analyses were performed on the whole set of data and separate analyses were conducted after stratification for study design, geographic location, use of hormone replacement therapy (HRT), tumor estrogen receptor status (ER+ or ER-), progesterone receptor status (PGR+ or PGR-), body mass index (BMI), smoker status, zinc or iron intake. Results: No statistically significant increased risk of breast cancer was observed when all studies were combined (mRR=1.03; 95% confidence interval [CI]: 0.89-1.19). Several sources of heterogeneity and inconsistency were identified, including smoker status, HRT use, BMI, zinc and iron intake. Inconsistency was also strongly reduced when only considering ER-, PGR-, tumors subgroups from USA and from Japan. The risks were, however, not substantially modified after stratifications. No evidence of publication bias was found. Conclusion: The present study does not provide support for the hypothesis that dietary exposure to Cd increases the risk of breast cancer in postmenopausal women. Misclassification in dietary Cd assessment in primary studies could have biased the results towards a finding of no association.
    Full-text · Article · Oct 2015 · Environment international
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    • "Cd is classified as a group I carcinogen by the International Agency of Research on Cancer (IARC, 1993). The cytotoxicity caused by Cd depends on its ability to bind to estrogen receptors (ERs), thereby mimicking the effects of estrogenic hormones, for which it is classified along with other metals like Cr, Hg and Cu (Darbre, 2006; Johnson et al., 2003; Martínez-Campa et al., 2006). A large number of studies reported that, in some cell types, low concentrations of Cd promote DNA synthesis, enhance the expression of several classes of genes (e.g. "
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    ABSTRACT: Cigarette smoking is a crucial factor in the development and progression of multiple cancers including breast. Here, we report that repeated exposure to a fixed, low dose of cigarette smoke condensate (CSC) prepared from Indian cigarettes is capable of transforming normal breast epithelial cells, MCF-10A, and delineate the biochemical basis for cellular transformation. CSC transformed cells (MCF-10A-Tr) were capable of anchorage-independent growth, and their anchorage dependent growth and colony forming ability were higher compared to the non-transformed MCF-10A cells. Increased expression of biomarkers representative of oncogenic transformation (NRP-1, Nectin-4), and anti-apoptotic markers (PI3K, AKT, NFκB) were also noted in the MCF-10A-Tr cells. Short tandem repeat (STR) profiling of MCF-10A and MCF-10A-Tr cells revealed that transformed cells acquired allelic variation during transformation, and had become genetically distinct. MCF-10A-Tr cells formed solid tumors when implanted into the mammary fat pads of Balb/c mice. Data revealed that CSC contained approximately 1.011μg Cd per cigarette equivalent, and Cd (0.0003μg Cd/1x10(7) cells) was also detected in the lysates from MCF-10A cells treated with 25μg/mL CSC. In similar manner to CSC, CdCl2 treatment in MCF-10A cells caused anchorage independent colony growth, higher expression of oncogenic proteins and increased PI3K-AKT-NFκB proteins expression. An increase in the expression of PI3K-AKT-NFκB was also noted in the mice xenografts. Interestingly, it was noted that CSC and CdCl2 treatment in MCF-10A cells increased ROS. Collectively, results suggest that heavy metals present in cigarettes of Indian origin may substantially contribute to tumorigenesis by inducing intercellular ROS accumulation and increased expression of PI3K,AKT and NFκB proteins.
    Full-text · Article · Oct 2013 · Toxicology and Applied Pharmacology
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    • "Cadmium is a ubiquitous carcinogenic pollutant as already mentioned, with multiple biological effects on living cells and various case studies have correlated its exposure to breast cancer [2, 29, 45, 46]. These studies observed a significant increased risk of breast cancer in patients with higher urinary cadmium concentration. "
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    ABSTRACT: The increased rate of breast cancer incidences especially among postmenopausal women has been reported in recent decades. Despite the fact that women who inherited mutations in the BRCA1 and BRCA2 genes have a high risk of developing breast cancer, studies have also shown that significant exposure to certain metal compounds and organic solvents also increases the risks of mammary gland carcinogenesis. While physiological properties govern the uptake, intracellular distribution, and binding of metal compounds, their interaction with proteins seems to be the most relevant process for metal carcinogenicity than biding to DNA. The four most predominant mechanisms for metal carcinogenicity include (1) interference with cellular redox regulation and induction of oxidative stress, (2) inhibition of major DNA repair, (3) deregulation of cell proliferation, and (4) epigenetic inactivation of genes by DNA hypermethylation. On the other hand, most organic solvents are highly lipophilic and are biotransformed mainly in the liver and the kidney through a series of oxidative and reductive reactions, some of which result in bioactivation. The breast physiology, notably the parenchyma, is embedded in a fat depot capable of storing lipophilic xenobiotics. This paper reviews the role of metal compounds and organic solvents in breast cancer development.
    Full-text · Article · May 2013
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