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 natur al epithelium has been removed, where they reform an epithelium in whi ch a few cells express the oncogene. Genes can be expressed in other t issues in a similar way. A wide variety of oncogenes have a clearly ob servable effect on the pattern of growth of mammary epithelium. Expres sion of individual oncogenes usually produces stable, characteristic p atterns of abnormal growth that can be regarded as preneoplastic state s. Different oncogenes produce a very diverse variety of such growth p atterns, 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 cell s, suggesting that they promote clonal expansion, whereas others give focal lesions. Oncogene co-operation can be studied by introducing fur ther oncogenes into preneoplastic epithelium, for example the introduc tion of ras into epithelium that already expresses activated myc gives tumours. The effects of both neu/c-erbB2 and myc on mouse mammary epi thelium may mimic events in human breast, encouraging the hope that th is will prove a way to model human breast cancer. The tissue reconstit ution approach promises to reconstruct tumour development in more deta il 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 t heir normal neighbours.