Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
}
TY - JOUR
T1 - Genotoxins and the initiation of sporadic breast cancer.
AU - Martin, Francis L.
PY - 2001/3
Y1 - 2001/3
N2 - Breast cancer is the most frequently diagnosed female malignancy world-wide. The aetiology of the majority of cases remains obscure and the only genotoxin as yet known to initiate breast cancer is ionizing radiation. High penetrance susceptibility genes probably account for no more than 5–10% of cases. The breast, which consists of 70–90% adipose tissue, has a unique morphological structure. Dispersed within it are the functional elements that are lined with cancer-susceptible epithelial cells. Numerous dietary and/or environmental fat-soluble compounds are known to be rodent mammary carcinogens. Extracts of lipid obtained following collagenase digestion of elective reduction mammoplasty tissues from UK resident women showed activity in short-term genotoxicity assays in 40% of cases. More active lipid extracts tended to come from donors whose human mammary epithelial cells (HMECs) exhibited pre-existing DNA single-strand breaks (SSBs). Lipid extracts also induced morphological transformation of mammalian cells in vitro. To increase cohort size, extracts of UK breast milk were examined for genotoxicity and similar activity profiles were observed. Viable cells, a large percentage of which were HMECs, were recovered from breast milk and examined for pre-existing SSBs and for the ability of the donor's own milk extract to induce SSBs. Again, donors whose untreated cells contained the most SSBs tended to yield genotoxic breast milk extracts. Breast milk cells were also able to activate rodent mammary carcinogens to DNA-damaging species. These studies provide good evidence for in vivo exposure of HMECs to genotoxic agents years before the peak in occurrence of sporadic breast cancer. Work is in progress to characterize these agents and to determine their possible role in breast cancer aetiology.
AB - Breast cancer is the most frequently diagnosed female malignancy world-wide. The aetiology of the majority of cases remains obscure and the only genotoxin as yet known to initiate breast cancer is ionizing radiation. High penetrance susceptibility genes probably account for no more than 5–10% of cases. The breast, which consists of 70–90% adipose tissue, has a unique morphological structure. Dispersed within it are the functional elements that are lined with cancer-susceptible epithelial cells. Numerous dietary and/or environmental fat-soluble compounds are known to be rodent mammary carcinogens. Extracts of lipid obtained following collagenase digestion of elective reduction mammoplasty tissues from UK resident women showed activity in short-term genotoxicity assays in 40% of cases. More active lipid extracts tended to come from donors whose human mammary epithelial cells (HMECs) exhibited pre-existing DNA single-strand breaks (SSBs). Lipid extracts also induced morphological transformation of mammalian cells in vitro. To increase cohort size, extracts of UK breast milk were examined for genotoxicity and similar activity profiles were observed. Viable cells, a large percentage of which were HMECs, were recovered from breast milk and examined for pre-existing SSBs and for the ability of the donor's own milk extract to induce SSBs. Again, donors whose untreated cells contained the most SSBs tended to yield genotoxic breast milk extracts. Breast milk cells were also able to activate rodent mammary carcinogens to DNA-damaging species. These studies provide good evidence for in vivo exposure of HMECs to genotoxic agents years before the peak in occurrence of sporadic breast cancer. Work is in progress to characterize these agents and to determine their possible role in breast cancer aetiology.
U2 - 10.1093/mutage/16.2.155
DO - 10.1093/mutage/16.2.155
M3 - Journal article
VL - 16
SP - 155
EP - 161
JO - Mutagenesis
JF - Mutagenesis
SN - 1464-3804
IS - 2
ER -