Increased formation of micronuclei after hormonal stimulation of cell proliferation in human breast cancer cells

The carcinogenicity of sex hormones is considered to be the result of a com bination of genotoxic and epigenetic modes of action, For estrogens, genoto xic activities include DNA damage by reactive metabolites and indirect geno toxicity by redox cycling and production of reactive oxygen species, Here, we present data on the induction of micronuclei in estrogen receptor-positi ve (MCF-7) and -negative (MDA) human breast cancer cell lines treated with estradiol to support an additional mechanism of chromosomal damage. MCF-7 c ells, but not MDA cells, treated with estradiol in the picomolar concentrat ion range showed an increase in micronucleus formation which correlated wit h the estradiol-induced cell proliferation. Addition of the specific estrad iol-receptor antagonist hydroxytamoxifen suppressed the estradiol-induced f ormation of micronuclei in MCF-7 cells, Increased frequencies were also see n after normalization of the data to the number of cell divisions by additi onal treatment of the cells with cytochalasin B, Thus, formation of micronu clei was not due to the chromosomal damaging activity of estradiol, The ind uced genomic damage may be explained by a hormone-specific forcing of respo nsive cells through the cell cycle, thereby overriding checkpoints operatin g under homeostatic control of the fell cycle.