Genotoxins and the initiation of sporadic breast cancer

Breast cancer is the most frequently diagnosed female malignancy world-wide . The aetiology of the majority of cases remains obscure and the only genot oxin as yet known to initiate breast cancer is ionizing radiation, High pen etrance susceptibility genes probably account for no more than 5-10% of cas es, The breast, which consists of 70-90% adipose tissue, has a unique morph ological structure. Dispersed within it are the functional elements that ar e lined with cancer-susceptible epithelial cells. Numerous dietary and/or e nvironmental fat-soluble compounds are known to be rodent mammary carcinoge ns. Extracts of lipid obtained following collagenase digestion of elective reduction mammoplasty tissues from UK resident women showed activity in sho rt-term genotoxicity assays in 40% of cases. More active lipid extracts ten ded to come from donors whose human mammary epithelial cells (HMECs) exhibi ted pre-existing DNA single-strand breaks (SSBs). Lipid extracts also induc ed morphological transformation of mammalian cells in vitro. To increase co hort size, extracts of UK breast milk were examined for genotoxicity and si milar activity profiles were observed. Viable cells, a large percentage of which were HMECs, were recovered from breast milk and examined for pre-exis ting SSBs and for the ability of the donor's own milk extract to induce SSB s. Again, donors whose untreated cells contained the most SSBs tended to yi eld genotoxic breast milk extracts, Breast milk cells were also able to act ivate rodent mammary carcinogens to DNA-damaging species. These studies pro vide good evidence for in vivo exposure of HMECs to genotoxic agents years before the peak in occurrence of sporadic breast cancer, Work is in progres s to characterize these agents and to determine their possible role in brea st cancer aetiology.