Estrogen Receptor Abstracts 10

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The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not
            (Aquino et al., 2012) Download
During the past half-century, incidences of breast cancer have increased globally. Various factors--genetic and environmental--have been implicated in the initiation and progression of this disease. One potential environmental risk factor that has not received a lot of attention is the exposure to heavy metals. While several mechanisms have been put forth describing how high concentrations of heavy metals play a role in carcinogenesis, it is unclear whether chronic, low-level exposure to certain heavy metals (i.e., cadmium and nickel) can directly result in the development and progression of cancer. Cadmium and nickel have been hypothesized to play a role in breast cancer development by acting as metalloestrogens--metals that bind to estrogen receptors and mimic the actions of estrogen. Since the lifetime exposure to estrogen is a well-established risk factor for breast cancer, anything that mimics its activity will likely contribute to the etiology of the disease. However, heavy metals, depending on their concentration, are capable of binding to a variety of proteins and may exert their toxicities by disrupting multiple cellular functions, complicating the analysis of whether heavy metal-induced carcinogenesis is mediated by the estrogen receptor. The purpose of this review is to discuss the various epidemiological, in vivo, and in vitro studies that show a link between the heavy metals, cadmium and nickel, and breast cancer development. We will particularly focus on the studies that test whether these two metals act as metalloestrogens in order to assess the strength of the data supporting this hypothesis.

Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.
            (Asara et al., 2013) Download
Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd.

Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial.
            (Badwe et al., 2011) Download
PURPOSE:  Many nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669). PATIENTS AND METHODS:  One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned. RESULTS:  At a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04). CONCLUSION:  A single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high.


 

Metals and breast cancer.
            (Byrne et al., 2013) Download
Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. The metalloestrogens fall into two subclasses: metal/metalloid anions and bivalent cationic metals. The metal/metalloid anions include compounds such as arsenite, nitrite, selenite, and vanadate while the bivalent cations include metals such as cadmium, calcium, cobalt, copper, nickel, chromium, lead, mercury, and tin. The best studied metalloestrogen is cadmium. It is a heavy metal and a prevalent environmental contaminant with no known physiological function. This review addresses our current understanding of the mechanism by which cadmium and the bivalent cationic metals activate estrogen receptor-α. The review also summarizes the in vitro and in vivo evidence that cadmium functions as an estrogen and the potential role of cadmium in breast cancer.

Cadmium--a metallohormone?
            (Byrne et al., 2009) Download
Cadmium is a heavy metal that is often referred to as the metal of the 20th century. It is widely used in industry principally in galvanizing and electroplating, in batteries, in electrical conductors, in the manufacture of alloys, pigments, and plastics, and in the stabilization of phosphate fertilizers. As a byproduct of smelters, cadmium is a prevalent environmental contaminant. In the general population, exposure to cadmium occurs primarily through dietary sources, cigarette smoking, and, to a lesser degree, drinking water. Although the metal has no known physiological function, there is evidence to suggest that the cadmium is a potent metallohormone. This review summarizes the increasing evidence that cadmium mimics the function of steroid hormones, addresses our current understanding of the mechanism by which cadmium functions as a hormone, and discusses its potential role in development of the hormone dependent cancers.

Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1 (MKP-1/DUSP1).
            (Chen et al., 2011) Download
The roles of progesterone (P(4)) and of progesterone receptor (PR) in development and pathogenesis of breast cancer remain unclear. In this study, we observed that treatment of T47D breast cancer cells with progestin antagonized effects of fetal bovine serum (FBS) to stimulate cell proliferation, whereas siRNA-mediated knockdown of endogenous PR abrogated progestin-mediated anti-proliferative effects. To begin to define mechanisms for the anti-proliferative action of P(4)/PR, we considered the role of MAPK phosphatase 1 (MKP-1/DUSP1), which catalyzes dephosphorylation and inactivation of MAPKs. Progestin treatment of T47D cells rapidly induced MKP-1 expression in a PR-dependent manner. Importantly, P(4) induction of MKP-1 was associated with reduced levels of phosphorylated ERK1/2, whereas siRNA knockdown of MKP-1 blocked progestin-mediated ERK1/2 dephosphorylation and repression of FBS-induced cell proliferation. The importance of PR in MKP-1 expression was supported by findings that MKP-1 and PR mRNA levels were significantly correlated in 30 human breast cancer cell lines. By contrast, no correlation was observed with the glucocorticoid receptor, a known regulator of MKP-1 in other cell types. ChIP and luciferase reporter assay findings suggest that PR acts in a ligand-dependent manner through binding to two progesterone response elements downstream of the MKP-1 transcription start site to up-regulate MKP-1 promoter activity. PR also interacts with two Sp1 sites just downstream of the transcription start site to increase MKP-1 expression. Collectively, these findings suggest that MKP-1 is a critical mediator of anti-proliferative and anti-inflammatory actions of PR in the breast.

Investigations on the estrogenic activity of the metallohormone cadmium in the rat intestine
            (Hofer et al., 2010) Download
Cadmium (Cd), a toxic heavy metal and an important environmental pollutant, is now also regarded as potential endocrine disruptor. Its estrogenic effects have been examined so far just in classical target tissues, e.g. uterus, and mostly upon intraperitoneal (i.p.) injection of CdCl(2). Yet, estrogen receptors are also expressed in the gut, and food is the main source of cadmium intake in the general population. Therefore, possible estrogenic effects were now investigated in the intestine of ovariectomized Wistar rats after oral short- and long-term administration of CdCl(2) (0.05-4 mg/kg bw on 3 days by gavage and 0.4-9 mg/kg bw for 4 weeks in drinking water) or upon i.p. injection (0.00005-2 mg CdCl(2)/kg bw), and compared to steroid estrogen (estradiol or ethinylestradiol) treated groups. Analysis of Cd in kidneys and small intestine by atomic absorption spectrometry showed dose-dependent increases in tissue levels with rather high Cd concentrations in the gut, both after oral and i.p. administration. Expression of metallothionein (MT1a), a typical metal response parameter, was clearly induced in kidney and small intestine of several CdCl(2) treated groups, but also notably increased by steroid estrogens. Levels of estrogen-regulated genes, i.e. pS2/TFF1, vitamin D receptor (VDR), and estrogen receptor alpha and beta (ER alpha/beta) were studied as parameters of hormonal activity: The intestinal mRNA expression of pS2/TFF1 was significantly decreased in the estrogen reference groups, but also after single i.p. injection and oral long-term administration of CdCl(2). In contrast, the mRNA and protein expression of the VDR were unaffected by long-term administration of Cd via drinking water. We detected expression of ERbeta, but not ERalpha in the small intestine of OVX rats. ERbeta mRNA and protein expression were significantly down-regulated by Cd, similar to the ethinylestradiol reference group. The mRNA expression and immunostaining of proliferating cell nuclear antigen (PCNA), as an index for cell proliferation, revealed decreases after long-term administration of Cd and ethinylestradiol. In summary, cadmium exposure was shown to modulate molecular and functional parameters of estrogenicity in the intestinal tract of OVX rats. As the intestine is known to express predominantly ERbeta, and is an important site of interaction with dietary contaminants, it is indicated to further investigate specific molecular mechanisms of cadmium and estrogen receptor interactions in more detail.

Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways.
            (Kerdivel et al., 2013) Download
In all vertebrate species, estrogens play a crucial role in the development, growth, and function of reproductive and nonreproductive tissues. A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Some of these compounds have been shown to induce adverse effects on human and animal health, and some compounds are suspected to contribute to diverse disease development. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel of in vivo and in vitro bioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. In this paper, we discuss different molecular actions of some of the major xenoestrogens found in food or the environment, and we summarize the current models used to evaluate environmental estrogens.

Progesterone receptor modulates ERα action in breast cancer.
            (Mohammed et al., 2015) Download
Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.


 

Cadmium mimics estrogen-driven cell proliferation and prolactin secretion from anterior pituitary cells.
            (Ronchetti et al., 2013) Download
Cadmium (Cd) is a heavy metal of considerable occupational and environmental concern affecting wildlife and human health. Recent studies indicate that Cd, like other heavy metals, can mimic effects of 17β-estradiol (E2) involving E2 receptor (ER) activation. Lactotrophs, the most abundant cell type in anterior pituitary gland, are the main target of E2, which stimulates cell proliferation and increases prolactin secretion through ERα. The aim of this work was to examine whether Cd at nanomolar concentrations can induce cell proliferation and prolactin release in anterior pituitary cells in culture and whether these effects are mediated through ERs. Here we show that 10 nM Cd was able to stimulate lactotroph proliferation in anterior pituitary cell cultures from female Wistar rats and also in GH3 lactosomatotroph cell line. Proliferation of somatotrophs and gonadotrophs were not affected by Cd exposure. Cd promoted cell cycle progression by increasing cyclins D1, D3 and c-fos expression. Cd enhanced prolactin synthesis and secretion. Cd E2-like effects were blocked by the pure ERs antagonist ICI 182,780 supporting that Cd acts through ERs. Further, both Cd and E2 augmented full-length ERαexpression and its 46 kDa-splicing variant. In addition, when co-incubated Cd was shown to interact with E2 by inducing ERα mRNA expression which indicates an additive effect between them. This study shows for the first time that Cd at nanomolar concentration displays xenoestrogenic activities by inducing cell growth and stimulating prolactin secretion from anterior pituitary cells in an ERs-dependent manner. Cd acting as a potent xenoestrogen can play a key role in the aetiology of different pathologies of the anterior pituitary and in estrogen-responsive tissues which represent considerable risk to human health.

Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun
            (Siewit et al., 2010) Download
Cadmium is an environmental contaminant that enters the body through diet or cigarette smoke. It affects multiple cellular processes, including cell proliferation, differentiation, and apoptosis. Recently, cadmium has been shown to function as an endocrine disruptor, to stimulate estrogen receptor alpha (ERalpha) activity and promote uterine and mammary gland growth in mice. Although cadmium exposure has been associated with the development of breast cancer, the mechanism of action of cadmium remains unclear. To address this deficit, we examined the effects of cadmium treatment on breast cancer cells. We found that ERalpha is required for both cadmium-induced cell growth and modulation of gene expression. We also determined that ERalpha translocates to the nucleus in response to cadmium exposure. Additionally, we provide evidence that cadmium potentiates the interaction between ERalpha and c-Jun and enhances recruitment of this transcription factor complex to the proximal promoters of cyclin D1 and c-myc, thus increasing their expression. This study provides a mechanistic link between cadmium exposure and ERalpha and demonstrates that cadmium plays an important role in the promotion of breast cancer.

Cadmium a metalloestrogen: are we convinced
            (Silva et al., 2012) Download
Metalloestrogens are inorganic metal ions that bind to and activate oestrogen receptors. They are implicated in the aetiology of oestrogen-dependent diseases such as cancers of the breast and endometrium as well as endometriosis. Cadmium is one of the most studied metalloestrogens. In this review, scientific evidence for the oestrogenic effects of cadmium is critically evaluated to determine if there is sufficient evidence to support cadmium as an aetiological factor of oestrogen-dependent disease in humans. Results of the review indicated that, although the in vitro and in vivo evidence of the oestrogenic properties of cadmium was persuasive, evidence from population-based human studies remains conflicting. Considerable knowledge gaps exist on the potential oestrogenic effect of cadmium in humans. Research that focuses on bridging these knowledge gaps would be useful in preventing and managing oestrogen-dependent disease in humans.

Association between cadmium and breast cancer risk according to estrogen receptor and human epidermal growth factor receptor 2: epidemiological evidence.
            (Strumylaite et al., 2014) Download
The study aimed to examine the association between cadmium (Cd) and the risk of breast cancer according to estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). A hospital-based case-control study was carried out in 585 cases and 1,170 controls. Information on possible risk factors was collected via a structured questionnaire. Urinary Cd was determined by atomic absorption spectrometry. The ER and HER2 levels in tumor tissue were analyzed by immunohistochemistry. Logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for breast cancer by creatinine-adjusted urinary Cd. Women with greater creatinine-adjusted urine Cd (3rd quartile: 0.241-0.399 μg/g and 4th quartile: ≥ 0.4 μg/g) experienced 1.6 times higher risk of breast cancer compared with those having Cd concentration lower than 0.147 μg/g (1st quartile) [OR = 1.6, (95 % CI 1.19, 2.17) and OR = 1.62 (95 % CI 1.19, 2.21), respectively, P trend = 0.001] after adjustment for age and other confounders. Both ER+ and HER2- cases from the highest quartile of urine Cd exhibited approximately twice the breast cancer risk of those in the lowest quartile [OR = 1.9, (95 % CI 1.31, 2.74) and OR = 1.87, (95 % CI 1.33, 2.62), respectively, P trend <0.001) after adjustment for confounders. The data support cadmium as a risk factor for breast cancer, especially for both ER+ and HER2- cancer patients.


Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.
            (Vandenberg et al., 2012) Download
For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of "the dose makes the poison," because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.

 

Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells.
            (Zang et al., 2009) Download
Cadmium (Cd) has been shown to bind to the human estrogen receptor (ER), yet studies on Cd's estrogenic effects have yielded inconsistent results. In this study, we investigated the effects of Cd on DNA synthesis and its simultaneous effects on both genomic (mediated by nuclear ER (nER)) and non-genomic (mediated by membrane-bound ER (mER)) signaling in human breast cancer derived T47D cells. No effects on DNA synthesis were observed for non-cytotoxic concentrations of CdCl(2) (0.1-1000 nM), and Cd did not increase progesterone receptor (PgR) or pS2 mRNA levels. However, Cd stimulated phosphorylation of ERK1/2 MAPK, detectable following 10 min and 18 h of treatment. The sustained Cd-induced ERK1/2 phosphorylation was inhibited by the ER antagonist ICI 182,780, suggesting the involvement of ER. In addition, Cd enhanced DNA synthesis and pS2 mRNA levels in estrogen (10 pM estradiol) treated T47D cells. The MEK1/2 specific inhibitor U0126 blocked DNA synthesis stimulated by estradiol (E2) and the E2-Cd mixtures. These findings indicate that the ERK1/2 signaling is critical in E2-related DNA synthesis. The sustained ERK1/2 phosphorylation may contribute to the Cd-induced enhancement of DNA synthesis and pS2 mRNA in mixture with low-concentration E2.

A novel antiestrogenic mechanism in progesterone receptor-transfected breast cancer cells.
            (Zheng et al., 2005) Download
The expression of progesterone receptor (PR) is normally estrogen-dependent, and progesterone is only active in target cells following estrogen exposure. This study revealed that the effect of estrogen was markedly disrupted by estrogen-independent expression of PR. Transfection of PR in estrogen receptor (ER)-positive MCF-7 cells abolished the estradiol-17beta growth stimulatory effect that was observed in the parental cells and the vector-transfected controls in a ligand-independent manner. The antiestrogenic effect was also observed at the level of gene transcription. Estradiol-17beta (E2)-induced gene expression of pS2 and GREB1 was impaired by 50-75% after 24-72 h of E2 treatment in PR-transfected cells. Promoter interference assay revealed that PR transfection drastically inhibited E2-mediated ER binding to estrogen response elements (ERE). The antiestrogenic effects of transfected PR are associated with enhanced metabolism of E2. HPLC analysis of [3H]E2 in the samples indicated that the percentage of [3H]E2 metabolized by PR-transfected cells in 6 h is similar to that by vector-transfected control cells in 24 h (77 and 80%, respectively). The increased metabolism of E2 may, in turn, be caused by increased cellular uptake of E2, as demonstrated by whole cell binding of [3H]E2. The findings open up a new window for a hitherto unknown functional relationship between the PR and ER. The antiestrogenic effect of transfected PR also provides a potential therapeutic strategy for estrogen-dependent breast cancer.

 


References

Aquino, NB, et al. (2012), ‘The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not’, J Environ Sci Health C Environ Carcinog Ecotoxicol Rev, 30 (3), 189-224. PubMed: 22970719
Asara, Y, et al. (2013), ‘Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.’, Int J Mol Sci, 14 (8), 16600-16. PubMed: 23941782
Badwe, R, et al. (2011), ‘Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial.’, J Clin Oncol, 29 (21), 2845-51. PubMed: 21670457
Byrne, C, et al. (2013), ‘Metals and breast cancer.’, J Mammary Gland Biol Neoplasia, 18 (1), 63-73. PubMed: 23338949
Byrne, C., et al. (2009), ‘Cadmium--a metallohormone?’, Toxicol Appl Pharmacol, 238 (3), 266-71. PubMed: 19362102
Chen, CC, DB Hardy, and CR Mendelson (2011), ‘Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1 (MKP-1/DUSP1).’, J Biol Chem, 286 (50), 43091-102. PubMed: 22020934
Hofer, N., et al. (2010), ‘Investigations on the estrogenic activity of the metallohormone cadmium in the rat intestine’, Arch Toxicol, 84 (7), 541-52. PubMed: 20186393
Kerdivel, G, D Habauzit, and F Pakdel (2013), ‘Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways.’, Int J Endocrinol, 2013 501851. PubMed: 23737774
Mohammed, H, et al. (2015), ‘Progesterone receptor modulates ERα action in breast cancer.’, Nature, 523 (7560), 313-17. PubMed: 26153859
Ronchetti, SA, et al. (2013), ‘Cadmium mimics estrogen-driven cell proliferation and prolactin secretion from anterior pituitary cells.’, PLoS One, 8 (11), e81101. PubMed: 24236210
Siewit, C. L., et al. (2010), ‘Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun’, Mol Endocrinol, 24 (5), 981-92. PubMed: 20219890
Silva, N, et al. (2012), ‘Cadmium a metalloestrogen: are we convinced’, J Appl Toxicol, 32 (5), 318-32. PubMed: 22161274
Strumylaite, L, et al. (2014), ‘Association between cadmium and breast cancer risk according to estrogen receptor and human epidermal growth factor receptor 2: epidemiological evidence.’, Breast Cancer Res Treat, 145 (1), 225-32. PubMed: 24692081
Vandenberg, LN, et al. (2012), ‘Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.’, Endocr Rev, 33 (3), 378-455. PubMed: 22419778
Zang, Y, S Odwin-Dacosta, and JD Yager (2009), ‘Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells.’, Toxicol Lett, 184 (2), 134-38. PubMed: 19041697
Zheng, ZY, et al. (2005), ‘A novel antiestrogenic mechanism in progesterone receptor-transfected breast cancer cells.’, J Biol Chem, 280 (17), 17480-87. PubMed: 15728178