Oestrogens induce G(1) arrest in benzo[a]pyrene-treated MCF-7 breast cells whilst enhancing genotoxicity and clonogenic survival.
Carcinogens, such as benzo[a]pyrene (B[a]P), allow cells to evade G(1) arrest (the stealth property), thus increasing the chance that DNA damage will ultimately result in transformation. In this study we have investigated the effects of B[a]P in MCF-7 cells incubated in the presence or absence of oestrogens (beta-oestradiol, oestrone or oestriol). The cytokinesis block micronucleus assay was used to examine cells for chromosomal damage. Micronuclei were scored in 500 binucleate cells per treatment. Increased micronucleus formation (3-fold) occurred following 24 h treatment with 10(-6) M B[a]P alone. Following co-treatment with either 10(-9) M beta-oestradiol, 10(-8) M oestrone or 10(-8) M oestriol, 2- to 3-fold increases in micronuclei were observed with 10(-8) M B[a]P. When MCF-7 cells were pre-incubated for 96 h with 10(-9) M beta-oestradiol, 10(-8) M oestrone or 10(-8) M oestriol prior to the addition of B[a]P for 24 h, up to a 5-fold enhanced sensitivity to micronucleus formation was observed with beta-oestradiol and oestrone, while oestriol appeared to reduce levels of micronucleus formation. B[a]P-induced decreases in cell proliferation (per cent binucleate cells) and plating efficiency were reversed by all three oestrogens. Analysis of cell cycle distributions revealed that treatment with oestrogens or B[a]P alone did not induce marked effects on cell cycle distributions. However, in combination oestrogen and B[a]P induced increases in G(0)/G(1), decreases in S phase and increases in G(2)/M. This work suggests that whilst oestrogens appear to enhance carcinogen-induced DNA damage, they also appear, paradoxically, to trigger mechanisms that facilitate clonogenic survival, which may be relevant to breast cancer initiation.
Davis
Cordula
C
Department of Biological Sciences, IENS, Lancaster University, Lancaster LA1 4YQ, UK.
Bhana
Sara
S
Shorrocks
A Julie
AJ
Martin
Francis L
FL
D001564:Benzo(a)pyrene / Q000633:toxicity*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects*; D004338:Drug Combinations; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D009152:Mutagenicity Tests; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004338:Drug Combinations; D004967:Estrogens; D001564:Benzo(a)pyrene