17β-Estradiol is carcinogenic in human breast epithelial cells

Russo, José; Lareef, Mohamed H.; Tahin, Quivo Schwartzburd; Yun, Hu; Slater, Carolyn; Ao, Xiang; Russo, Irma H.

doi:10.1016/s0960-0760(01)00183-2

Cited by 79 publications

(89 citation statements)

References 60 publications

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“…67 The rates of 4-OHE 2 formation exceeded those of 2-OHE 2 formation by almost 4-fold in mammary fibroadenomas and adenocarcinomas, although the rates did not markedly differ in normal human mammary tissue. 68 We have found that mutations produced by E 2 and its metabolites were not prevented by the antiestrogen ICI182780, indicating that E 2 might act through an alternate non-ERa pathway, but we cannot rule out the intervention of ERb that is positive in these cells 8,9 or that specific receptors for 4-OHE 2 might be present and operational. 69 Other work has shown that 4-OHE 2 induces an estrogenic response in the uterus of ERa null mice, and this response was not inhibited by ICI182780.…”

Section: Discussionmentioning

confidence: 84%

“…17b-estradiol (E 2 ), being one of the most important etiological factors for the development and progression of BC. [2][3][4][5][6][7][8][9][10] The risk factors include high serum or urinary estrogen concentrations, [11][12][13] the early onset of menstruation, and late menopause, related to prolonged exposure to estrogens. 4,14 Although the precise molecular mechanisms by which E 2 induces breast cancer have not been completely understood, the estrogen implication in breast cancer has been associated mostly with the estrogen receptor (ER) that mediates cell proliferation.…”

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confidence: 99%

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Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Fernandez

Russo

2005

Intl Journal of Cancer

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110

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An elevated incidence of breast cancer in women has been associated with prolonged exposure to high levels of estrogens. Our laboratory demonstrated that treatment of the immortalized human breast epithelial cells MCF-10F with 17b-estradiol (E 2 ), 4-hydroxyestradiol (4-OHE 2 ) or 2-hydroxyestradiol (2-OHE 2 ) induces phenotypical changes indicative of neoplastic transformation. MCF-10F cells treated with E 2 , 4-OHE 2 or 2-OHE 2 formed colonies in agar methocel and lost their ductulogenic capacity in collagen, expressing phenotypes similar to those induced by the carcinogen benzo[a]pyrene. To investigate whether the transformation phenotypes were associated with genomic changes, cells treated with E 2 , 4-OHE 2 or 2-OHE 2 at different doses were analyzed using microsatellite markers. Since microsatellite instability (MSI) and loss of heterozygosity (LOH) in chromosomes 13 and 17 have been reported in human breast carcinomas, we tested these parameters in MCF-10F cells treated with E 2 , 2-OHE 2 , or 4-OHE 2 alone or in combination with the antiestrogen ICI182780. MCF-10F cells treated with E 2 or 4-OHE 2 , either alone or in combination with ICI182780, exhibited LOH in the region 13q12.3 with the marker D13S893 located at 0.8 cM telomeric to BRCA2. Cells treated with E 2 or 4-OHE 2 at doses of 0.007 and 70 nM and 2-OHE 2 only at a higher dose (3.6 lM) showed a complete loss of 1 allele with D13S893. For chromosome 17, differences were found using the marker TP53-Dint located in exon 4 of p53. Cells treated with E 2 or 4-OHE 2 at doses of 0.007 nM and 70 nM and 2-OHE 2 only at a higher dose (3.6 lM) exhibited a 5 bp deletion in p53 exon 4. Our results show that E 2 and its catechol estrogen metabolites are mutagenic in human breast epithelial cells. ICI182780 did not prevent these mutations, indicating that the carcinogenic effect of E 2 is mainly through its reactive metabolites 4-OHE 2 and 2-OHE 2, with 4-OHE 2 and E 2 being mutagenic at lower doses than 2-OHE 2 . ' 2005 Wiley-Liss, Inc.Key words: breast cancer; estrogen; 4-OHE 2 ; 2-OHE 2 ; cell transformation Breast cancer (BC) is the most commonly occurring neoplasm and the second most frequent cause of cancer death among women in the United States. 1 There is a substantial amount of epidemiological, clinical and experimental evidence pointing to estrogens, e.g. 17b-estradiol (E 2 ), being one of the most important etiological factors for the development and progression of BC. 2-10 The risk factors include high serum or urinary estrogen concentrations, 11-13 the early onset of menstruation, and late menopause, related to prolonged exposure to estrogens. 4,14 Although the precise molecular mechanisms by which E 2 induces breast cancer have not been completely understood, the estrogen implication in breast cancer has been associated mostly with the estrogen receptor (ER) that mediates cell proliferation. 15,16 The direct role of estrogens as tumor initiators has been supported by the evidence that E 2 , catechol estrogens (CEs), and their quinone derivatives ...

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Fernandez

Russo

2005

Intl Journal of Cancer

Self Cite

110

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“…An approximately million times higher concentration of 2-OHE 2 is needed to transform these cells (22,23). Transformation occurs even in the presence of the antiestrogen ICI-182,780 (24), indicating that transformation does not proceed through estrogen receptor-mediated events (25).…”

Section: Discussionmentioning

confidence: 99%

“…These adducts generate apurinic sites that may lead to cancer-initiating mutations (17)(18)(19), which transform cells (22)(23)(24)(25), thereby initiating cancer.…”

Section: Introductionmentioning

confidence: 99%

The Greater Reactivity of Estradiol-3,4-quinone vs Estradiol-2,3-quinone with DNA in the Formation of Depurinating Adducts: Implications for Tumor-Initiating Activity

Zahid

Kohli

Saeed

et al. 2005

Chem. Res. Toxicol.

151

207

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Strong evidence supports the idea that specific metabolites of estrogens, mainly catechol estrogen-3,4-quinones, can react with DNA to become endogenous initiators of breast, prostate, and other human cancers. Oxidation of the catechol estrogen metabolites 4-hydroxyestradiol (4-OHE 2 ) and 2-OHE 2 leads to the quinones, estradiol-3,4-quinone (E 2 -3,4-Q) and estradiol-2,3-quinone (E 2 -2,3-Q), respectively. The reaction of E 2 -3,4-Q with DNA affords predominantly the depurinating adducts 4-OHE 2 -1-N3Ade and 4-OHE 2 -1-N7Gua, whereas the reaction of E 2 -2,3-Q with DNA yields the newly synthesized depurinating adduct 2-OHE 2 -6-N3Ade. The N3Ade adducts are lost from DNA by rapid depurination, while the N7Gua adduct is lost from DNA with a half-life of ∼3 h at 37°C. To compare the relative reactivity of E 2 -3,4-Q and E 2 -2,3-Q, the compounds were reacted individually with DNA for 0.5-20 h at 37°C, as well as in mixtures (3:1, 1:1, 1:3, and 5:95) for 10 h at 37°C. Depurinating and stable adducts were analyzed. In similar experiments, the relative reactivity of 4-OHE 2 and 2-OHE 2 with DNA was determined after activation by lactoperoxidase, tyrosinase, prostaglandin H synthase (PHS), or 3-methylcholanthreneinduced rat liver microsomes. Starting with the quinones, the levels of depurinating adducts formed from E 2 -3,4-Q were much higher than that of the depurinating adduct from E 2 -2,3-Q. Similar results were obtained with lactoperoxidase or tyrosinase-catalyzed oxidation of 4-OHE 2 and 2-OHE 2 , whereas with activation by PHS or microsomes, a relatively higher amount of the depurinating adduct from E 2 -2,3-Q was detected. These results demonstrate that the E 2 -3,4-Q is much more reactive with DNA than E 2 -2,3-Q. The relative reactivities of E 2 -3,4-Q and E 2 -2,3-Q to form depurinating adducts correlate with the carcinogenicity, mutagenicity, and cell-transforming activity of their precursors, the catechol estrogens 4-OHE 2 and 2-OHE 2 . This is essential information for understanding the cancer risk posed by oxidation of the two catechol estrogens.

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“…A recent study on human epithelial breast cells showed a potential effect of estradiol on neoplastic transformation. 21 This raises the concern whether exposure to estradiol might confer a higher risk of breast cancer than conjugated estrogens and may suggest that in the future these 2 types of estrogen should be analyzed separately as different exposure groups. However, the recent study from the United Kingdom found both types of estrogens to increase the risk of breast cancer equally, but there was the possibility of women having switched preparations in about 1/3 of the total population, which might have introduced some bias.…”

Section: Discussionmentioning

confidence: 99%

Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe

Stahlberg

Pedersen

Lynge

et al. 2004

Intl Journal of Cancer

198

124

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17β-Estradiol is carcinogenic in human breast epithelial cells

Cited by 79 publications

References 60 publications

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

The Greater Reactivity of Estradiol-3,4-quinone vs Estradiol-2,3-quinone with DNA in the Formation of Depurinating Adducts: Implications for Tumor-Initiating Activity

Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe

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