Tissue reconstitution models of breast cancer

Oncogenes have been expressed in mammary epithelium by reconstituting epithelium in vivo from mammary cells. Genetically manipulated primary cultures are transplanted into a mammary fat pad from which the natural epithelium has been removed, where they reform an epithelium in which a few cells express the oncogene. Genes can be expressed in other tissues in a similar way. A wide variety of oncogenes have a clearly observable effect on the pattern of growth of mammary epithelium. Expression of individual oncogenes usually produces stable, characteristic patterns of abnormal growth that can be regarded as preneoplastic states. Different oncogenes produce a very diverse variety of such growth patterns, by altering branching pattern, inducing formation of alveoli, causing epithelium to multilayer and/or altering hormone dependence. Myc and wnt1 seem to enable cells to overgrow neighbouring normal cells, suggesting that they promote clonal expansion, whereas others give focal lesions. Oncogene co-operation can be studied by introducing further oncogenes into preneoplastic epithelium, for example the introduction of ras into epithelium that already expresses activated myc gives tumours. The effects of both neu/c-erbB2 and myc on mouse mammary epithelium may mimic events in human breast, encouraging the hope that this will prove a way to model human breast cancer. The tissue reconstitution approach promises to reconstruct tumour development in more detail than the transgenic systems are able to, showing the development of focal lesions, the restraining effects of normal on transformed cells and the expansion of clones of hyperplastic cells at the expense of their normal neighbours.