TY - JOUR

T1 - Oestrogens induce G1 arrest in benzo[a]pyrene-treated MCF-7 breast cells while enhancing genotoxicity and clonogenic survival.

AU - Davis, Cordula

AU - Bhana, Sara

AU - Shorrocks, A. Julie

AU - Martin, Francis L.

PY - 2003/9

Y1 - 2003/9

N2 - Carcinogens, such as benzo[a]pyrene (B[a]P), allow cells to evade G1 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 (ß-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 ß-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 ß-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 ß-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 G0/G1, decreases in S phase and increases in G2/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.

AB - Carcinogens, such as benzo[a]pyrene (B[a]P), allow cells to evade G1 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 (ß-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 ß-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 ß-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 ß-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 G0/G1, decreases in S phase and increases in G2/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.

U2 - 10.1093/mutage/17.5.431

DO - 10.1093/mutage/17.5.431

M3 - Journal article

VL - 17

SP - 431

EP - 438

JO - Mutagenesis

JF - Mutagenesis

SN - 1464-3804

IS - 5

ER -