Enzymatic regulation of estradiol-17β concentrations in human breast cancer cells

Adams, J.B.

doi:10.1007/bf01834620

Cited by 23 publications

(14 citation statements)

References 71 publications

(85 reference statements)

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“…The enzyme activity of wild type T-47D breast cancer cells was assessed by determining the ability of intact monolayers to convert added [3H]estrone to [3H]estradiol (33,34). For each experiment, stock cultures were harvested by trypsinization and seeded on culture dishes (60 x 15 mm, 2 x lo5 cells per dish) and cultured for 5 days in phenol red-free DMEM with 5% dcFCS and insulin (as in stock cultures).…”

Section: Methodsmentioning

confidence: 99%

Estrogen-Specific 17 -Hydroxysteroid Oxidoreductase Type 1 (E.C. 1.1.1.62) as a Possible Target for the Action of Phytoestrogens

Mäkelä

Poutanen

Lehtimäki

et al. 1995

Experimental Biology and Medicine

152

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Several plant estrogens, especially coumestrol and genistein, were found to reduce the conversion of [3H]estrone to [3H] 17 beta-estradiol catalyzed by estrogen-specific 17 beta-hydroxysteroid oxidoreductase Type 1 (E.C. 1.1.1.62) in vitro. Coumestrol, the most potent inhibitor in our experiments, is the best inhibitor of the enzyme known to date. All compounds with inhibitory effects were also estrogenic. However, structural demands for 17 beta-HSOR Type 1 inhibition and estrogenicity of tested compounds in breast cancer cells (judged by increased cell proliferation) were not identical. Zearalenone and diethylstilbestrol, both potent estrogens, did not inhibit 17 beta-HSOR Type 1. Thus, changes in the estrogen molecule may discriminate between active sites of 17 beta-HSOR Type 1 and estrogen binding sites of the ER. The effects of these compounds in vivo cannot be predicted on the basis of these results. Inhibition of 17 beta-HSOR Type 1 enzyme could lead to a decrease in the availability of the highly active endogenous estrogen. However, these compounds are estrogenic per se, and they may thus replace endogenous estrogens. Additional studies are needed to further understand the role of these plant estrogens in the etiology of hormone-dependent cancers. It is not easily conceivable how the chemopreventive action of Asian diets, possibly mediated by phytoestrogens in soya products, can be based on the inhibition of estrone reduction at the target cells by phytoestrogens or related compounds, unless they are "incomplete estrogens" (i.e., unable to induce all effects typical of endogenous estrogens).

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Section: Methodsmentioning

confidence: 99%

Estrogen-Specific 17 -Hydroxysteroid Oxidoreductase Type 1 (E.C. 1.1.1.62) as a Possible Target for the Action of Phytoestrogens

Mäkelä

Poutanen

Lehtimäki

et al. 1995

Experimental Biology and Medicine

152

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“…For example, effects of alcohol on breast cancer are hypothesized to be due to a variety of impacts on cellular signaling pathways, including increased circulating estrogen and androgen levels (Ginsburg et al 1995;Singletary and Gapstur 2001). Although the focus of research in this area has been on measuring circulating serum or urinary levels of endogenous hormones, it is important to note that human breast tissue can metabolize hormones and create its own local hormonal environment independent of circulating levels (Adams 1991;Adams et al 1992). Thus, effects of chemicals on the local hormone environment in the breast may be more relevant than effects on circulating hormone levels.…”

Section: Review | Environmental Pollutants and Breast Cancermentioning

confidence: 99%

Environmental pollutants and breast cancer.

Brody

Rudel

2003

Environ Health Perspect

284

190

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Breast cancer is the most common cancer in women and the leading cause of cancer death among women 35-54 years of age. Rising incidence, increased risk among migrants to higher risk regions, and poor prediction of individual risk have prompted a search for additional modifiable factors. Risk factors for breast cancer include reproductive characteristics associated with estrogen and other hormones, pharmaceutical hormones, and activities such as alcohol use and lack of exercise that affect hormone levels. As a result, investigation of hormonally active compounds in commercial products and pollution is a priority. Compounds that cause mammary tumors in animals are additional priorities. Animal models provide insight into possible mechanisms for effects of environmental pollutants on breast cancer and identify chemical exposures to target in epidemiologic studies. Although few epidemiologic studies have been conducted for chemical exposures, occupational studies show associations between breast cancer and exposure to certain organic solvents and polycyclic aromatic hydrocarbons (PAHs). Population-based studies have been limited to a few organochlorine compounds and PAHs and have been mostly negative. A variety of challenges in studies of breast cancer and the environment may have contributed to negative findings. Lack of exposure assessment tools and few hypothesis-generating toxicologic studies limit the scope of epidemiologic studies. Issues of timing with respect to latency and periods of breast vulnerability, and individual differences in susceptibility pose other challenges. Substantial work is needed in exposure assessment, toxicology, and susceptibility before we can expect a pay-off from large epidemiologic studies of breast cancer and environment.

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“…The sulfonation of E2 makes the compound more soluble for renal excretion as well as for the creation of inactive stores of sulfated E2 that can be desulfated by steroid sulfatases . Both the estrogen receptor (ER) and EST have affinities for E2 in the nanomolar range, thus suggesting that EST may play an important role in the regulation of estrogenic effects by controlling the levels of E2 (Adams 1991;Falany and Falany 1996). The ability of EST to mediate local estrogen concentration has been demonstrated in mice by gene disruption studies (Qian et al 2001;Tong and Song 2002).…”

mentioning

confidence: 99%

Crystallographic analysis of a hydroxylated polychlorinated biphenyl (OH-PCB) bound to the catalytic estrogen binding site of human estrogen sulfotransferase.

Shevtsov

Petrotchenko

Pedersen

et al. 2003

Environ Health Perspect

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Certain hydroxylated polychlorinated biphenyls (OH-PCBs) inhibit the human estrogen sulfotransferase (hEST) at subnanomolar concentrations, suggesting a possible pathway for PCB toxicity due to environmental exposure in humans. To address the structural basis of the inhibition, we have determined the crystal structure of hEST in the presence of the sulfuryl donor product 3´-phosphoadenosine 5´-phosphate and the OH-PCB 4,4´-OH 3,5,3´,5´-tetraCB. The OH-PCB binds in the estrogen binding site with the position of the first phenolic ring in an orientation similar to the phenolic ring of 17β-estradiol. Interestingly, the OH-PCB does not bind in a planar conformation, but rather with a 30-degree twist between the phenyl rings. The crystal structure of hEST with the OH-PCB bound gives physical evidence that certain OH-PCBs can mimic binding of estrogenic compounds in biological systems.

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Enzymatic regulation of estradiol-17β concentrations in human breast cancer cells

Cited by 23 publications

References 71 publications

Estrogen-Specific 17 -Hydroxysteroid Oxidoreductase Type 1 (E.C. 1.1.1.62) as a Possible Target for the Action of Phytoestrogens

Estrogen-Specific 17 -Hydroxysteroid Oxidoreductase Type 1 (E.C. 1.1.1.62) as a Possible Target for the Action of Phytoestrogens

Environmental pollutants and breast cancer.

Crystallographic analysis of a hydroxylated polychlorinated biphenyl (OH-PCB) bound to the catalytic estrogen binding site of human estrogen sulfotransferase.

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