Evidence for an Initiation Mechanism of 17β-Estradiol Carcinogenesis

Yu, Fu‐Li; Wang, Mian-Ying; Bender, Wanda

doi:10.1007/978-1-4612-2092-3_46

Cited by 4 publications

(10 citation statements)

References 8 publications

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“…Therefore, one of the important tests of our hypothesis is to determine whether E 1 and E 2 after DMDO activation are able to bind to DNA. In support to our hypothesis, we have found that 3 H‐labelled E 1 and E 2 are able to bind to both G‐C and A‐T containing DNAs but only after DMDO activation [10,11]. Additionally, the covalent binding nature of E 1 and E 2 to DNA after DMDO activation was further confirmed by 32 P‐post‐labelling analysis using calf thymus as well as several synthetic DNAs of a known base content and sequence [10,11].…”

Section: Introductionsupporting

confidence: 83%

“…Our earlier studies have concluded that E 2 , after activation by epoxidation, is able to bind to DNA‐forming DNA adducts both in vitro [10,11] and in vivo [13,14]. However, no functional tests have been conducted for these E 2 ‐DNA adducts on any of these substrate DNAs.…”

Section: Resultsmentioning

confidence: 99%

“…The procedure to activate E 2 using the specific epoxide‐forming oxidant DMDO was the same as described previously [6,10,11]. Briefly, aliquots of 1 ml of the freshly prepared DMDO were mixed with 1 mg E 2 at room temperature for 60 min with gentle shaking.…”

Section: Methodsmentioning

confidence: 99%

“…(c) The E 2 epoxide group, 5 μg of the plasmid DNA was incubated with 200 μg of the DMDO‐activated E 2 in the presence of 33% DMSO. The binding reaction for each group was carried out at room temperature for 1 h. The nuclease P1‐enhanced version of the 32 P‐post‐labelling technique was used for DNA adduct analysis [10,11]. Kodak XAR‐5 or Du Pont Cronex 4 X‐ray films and Du Pond Lightning Plus intensifying screens were used for the detection of DNA adducts after the films were exposed for 16 h at −80°C [10,11].…”

Section: Methodsmentioning

confidence: 99%

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The effect of 17β‐estradiol‐DNA adducts on the replication of exon # 5 of the human suppressor gene p53

Zheng

Wang

et al. 1999

FEBS Letters

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Using a PCR technique, exon # 5 of the human tumor suppressor gene p53 was amplified and ligated into the pCRII vector and transformed into Escherichia coli INVK KF' competent cells. The cloned exon # 5 was 184 bp long. Evidence is presented to show that after dimethyldioxirane epoxidation, 17L L-estradiol was able to form 17L L-estradiol-DNA adducts and to strongly inhibit the replication of the cloned exon # 5 producing smaller sizes of DNA fragments and introducing errors of incorporation at the 3P P-end of the terminating DNAs. The errors occurred mainly at the clusters of the complementary`G' and`A' bases on the template strand DNA, presumably, the major sites where the 17L L-estradiol-DNA adducts were formed.z 1999 Federation of European Biochemical Societies.

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Section: Introductionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The effect of 17β‐estradiol‐DNA adducts on the replication of exon # 5 of the human suppressor gene p53

Zheng

Wang

et al. 1999

FEBS Letters

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“…Using the same strain of rats, we found that when the female ACI rats were given intramammillary injections of E 2 or DMDO‐activated E 2 (i.e., E 2 epoxide), identical DNA adducts were formed in vivo , and the E 2 epoxide was at least 25 000 time more active than E 2 in the formation of DNA adducts in mammary glands (Figs 5,6). 28−30 Therefore, these in vitro and in vivo experiments have provided critical evidence in support of our proposed hypothesis of oestrogen epoxidation and the initiation of oestrogen carcinogenesis 13 …”

Section: β‐Estradiol Epoxidation As the Underlying Mechanism Of Brementioning

confidence: 52%

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

2002

Asia Pac J Clin Nutr

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Epidemiological and animal studies have indicated that 17beta-estradiol (E2) is involved in breast cancer; however, the mechanism is unclear. We found that E2 could be activated by epoxidation, resulting in its ability to inhibit nuclear DNA-dependent RNA synthesis, and to bind DNA, forming DNA adducts both in vitro and in vivo. Because epoxidation is required for the activation of many chemical carcinogens, including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene and aflatoxins, we proposed previously that E2 epoxidation is the underlying mechanism for the initiation of breast cancer. The first part of this review is to present the experimental evidence obtained from this laboratory in support of this hypothesis. Based on these newly discovered insights on E2 epoxidation and its initiation role in breast cancer carcinogenesis, a method to screen chemopreventive agents against breast cancer has been developed. This constitutes the second part of the review. Two examples will be used to illustrate the utility of this screening technique. The effect of fat on breast cancer has been a longstanding but unresolved issue. Epidemiological studies provide conflicting results regarding the association of dietary fat and breast cancer. Because vegetable oils contain various amount of mono- and polyunsaturated fatty acids, they are potential antioxidants. Data are presented to show that commercial vegetable oils, independent of their mono- or polyunsaturated fatty acid content, are all able to prevent the formation of E2 epoxide, as measured by the loss of the ability of E2 to inhibit nuclear RNA synthesis in vitro. Tamoxifen (TAM), an anti-estrogen used for breast cancer treatment, has recently been found to have a strong breast cancer preventive effect. The mechanism for this is unknown. Using the same screening technique, we found that when incubated together with E2 for epoxidation, TAM was able to prevent the formation of E2 epoxide, as evidenced by both the loss of the ability of E2 to inhibit nuclear RNA synthesis and the reduced binding of [3H]-labelled E2 to nuclear DNA in a dose-dependent manner. These experimental results suggest that the breast cancer preventive effect of TAM is to prevent the formation of E2 epoxide through a competitive epoxidation mechanism with E2.

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A proposed mechanism of tamoxifen in breast cancer prevention

Bender

2002

Cancer Detection and Prevention

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Evidence for an Initiation Mechanism of 17β-Estradiol Carcinogenesis

Cited by 4 publications

References 8 publications

The effect of 17β‐estradiol‐DNA adducts on the replication of exon # 5 of the human suppressor gene p53

The effect of 17β‐estradiol‐DNA adducts on the replication of exon # 5 of the human suppressor gene p53

17β‐Estradiol epoxidation as the molecular basis for breast cancer initiation and prevention

A proposed mechanism of tamoxifen in breast cancer prevention

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