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Carcinogenesis Advance Access originally published online on June 9, 2008
Carcinogenesis 2008 29(10):1862-1868; doi:10.1093/carcin/bgn138
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Estrogens and genomic instability in human breast cancer cells—involvement of Src/Raf/Erk signaling in micronucleus formation by estrogenic chemicals

Alena Kabil, Elisabete Silva and Andreas Kortenkamp*

The School of Pharmacy, University of London, Center for Toxicology 29–39 Brunswick Square, London WC1N 1AX, UK

* To whom correspondence should be addressed. Tel: +44 20 7753 5908; Fax: +44 20 7753 5811; Email: andreas.kortenkamp{at}pharmacy.ac.uk

Reports of the ability of estrogenic agents such as 17β-estradiol (E2), estriol (E3) and bisphenol A (BPA) to induce micronuclei (MN) in MCF-7 breast cancer cells have prompted us to investigate whether these effects are linked to activation of the estrogen receptor (ER) {alpha}. Coadministration of tamoxifen and the pure ER antagonist ICI 182 780 to cells treated with E2 and E3 did not lead to significant reductions in micronucleus frequencies. Since these antiestrogens interfere with the transcriptional activity of the ER and block promotion of ER-dependent gene expression, it appears that this process is not involved in micronucleus formation. However, ER activation also triggers rapid signaling via the Src/Raf/extracellular signal-regulated kinase (Erk) pathway. When MCF-7 cells were exposed to E2 and BPA in combination with the specific kinase inhibitors pyrazolopyrimidine and 2'-amino-3'-methoxyflavone, reductions in micronucleus frequencies occurred. These findings suggest that the Src/Raf/Erk pathway plays a role in micronucleus formation by estrogenic agents. Enhanced activation of the Src/Raf/Erk cascade disturbs the localization of Aurora B kinase to kinetochores, leading to a defective spindle checkpoint with chromosome malsegregation. Using antikinetochore CREST antibody staining, a high proportion of micronucleus containing kinetochores was observed, indicating that such processes are relevant to the induction of MN by estrogens. Our results suggest that estrogens induce MN by causing improper chromosome segregation, possibly by interfering with kinase signaling that controls the spindle checkpoint, or by inducing centrosome amplification. Our findings may have some relevance in explaining the effects of estrogens in the later stages of breast carcinogenesis.

Abbreviations: B[a]P, benzo[a]pyrene; BN, binucleated; BPA, bisphenol A; DMSO, dimethyl sulfoxide; E2, 17β-estradiol; E3, estriol; EGF, epidermal growth factor; ER, estrogen receptor {alpha}; Erk, extracellular signal-regulated kinase; EtOH, ethanol; FITC, fluorescein isothiocyanate; MAPK, mitogen-activated protein kinase; MN, micronuclei; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PD 98059, 2'-amino-3'-methoxyflavone; PP2, pyrazolopyrimidine; TAM, tamoxifen

Received January 10, 2008; revised April 30, 2008; accepted May 31, 2008.


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