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Title: Molecular mechanisms underlying estrogen-induced micronucleus formation in breast cancer cells
Author: Kabil, Alena
ISNI:       0000 0004 2673 3560
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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Molecular mechanisms underlying estrogen-induced micronucleus formation in breast cancer cells Aneuploidy, or numerical changes of chromosomes, has been documented in almost all solid tumours and the frequency of micronucleus formation is commonly taken as a biomarker of aneuploidy. An increasing number of observations suggest that exposure to physiologically relevant concentrations of steroidal estrogens gives rise to chromosomal impairments in estrogen receptor competent cells. Although the action of estrogenic compounds is well explained by their ability to bind and activate the estrogen receptor, there are still many uncertainties surrounding the mechanism underlying the ability of steroidal compounds to stimulate micronuclei formation. This has prompted us to investigate whether these effects are linked to activation of the estrogen receptor alpha. Co-administration of tamoxifen and the pure estrogen receptor antagonist ICI 182,780 to breast cancer MCF-7 cells with estrogenic agents did not lead to significant reductions in micronucleus frequencies. Since these anti-estrogens interfere with the transcriptional activity of the estrogen receptor and block promotion of estrogen receptor-dependent gene expression, it appears that this process is not involved in micronucleus formation. In addition to the classical activation of the estrogen receptor at the nuclear level, it is now accepted that estrogenic compounds can rapidly and transiently trigger a number of second-messenger signaling pathways, such as the MAPK cascade Erkl/2 and even their upstream effectors, such as the kinase Src and Raf. Therefore, we wanted to evaluate if the alternative mechanisms of estrogen receptor activation could be involved in the formation of micronuclei by estrogenic compounds. When MCF-7 cells were exposed to estrogenic agents in combination with the specific kinase inhibitors PP2 and PD 98059, reductions in micronucleus frequencies occurred. These findings suggest that the Src/Raf/Erk pathway plays a role in micronucleus formation by estrogenic compounds. Enhanced activation of the Src/Raf/Erk cascade disturbs the localisation of Aurora B kinase to kinetochores, leading to a defective spindle checkpoint with chromosome malsegregation. Further on, using anti-kinetochore CREST antibody staining, a high proportion of micronucleus containing kinetochores was observed when the breast cancer cells were treated with compounds able to activate non-genomic signaling pathways, indicating that such processes are relevant to the induction of micronuclei by estrogens. Our results suggest that estrogens induce micronuclei 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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available