locally secreted growth factors and extracellular matrix proteins in determining epithelial cell function. It is possible that local misregulation is actually the mechanism by which transformation of specific cells takes place. One negative aspect of organ culture is that the heterogeneity of cells means that certain effects need to be measured in situ on the cells, in addition to measuring factors released into the medium.

Nude Mouse Model

The athymic nude mouse model system is an immunologically incompetent mouse that does not reject tissue from other species. Normal mammary epithelium can grow in cleared fat pads of nude mice and forms normal ductal structures. Some breast cancer cell lines form tumors readily in these animals. Hence, the nude mouse provides a useful “in vivo/in vitro” system to study factors that contribute to tumor growth. Athymic mice do not secrete much estrogen because their ovaries undergo premature failure and thus exogenous estrogen must be given for tumor growth of human breast cell lines. This exogenous estrogen can act locally —that is, directly on the breast tumor cells. The model has also shown that mutagenesis by estrogen of human breast cancer cells can be potentiated by cotransplants of a pituitary cell line, GH3 cells, suggesting that a pituitary factor (not GH or prolactin) may also be necessary for this process (Dembinski et al., 1985).

The usefulness of the nude mouse is that the animal itself provides the “culture milieu” for its transplanted tissue, and this natural medium is renewed appropriately by the circulatory system. These culture conditions may simulate the intact mammary tissue better than in vitro conditions. Furthermore, given the mouse's low endogenous estrogen levels, this model may be valuable for studying the effects of cyclic administration of various oral contraceptives on normal mammary epithelium.

SUMMARY AND CONCLUSIONS

Although recent studies of mammary gland development, physiology, cell biology, and molecular biology have increased our knowledge considerably, there are no definitive answers as yet that enable us to understand, in all of its aspects, the biological etiology of breast cancer. A number of leads should be followed. Does the 16α-hydroxysteroid metabolic pathway lead to production of a hormone metabolite that binds the estrogen receptor more tightly than normal, leading to abnormal or enhanced gene products? Do exogenous



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