Ha-ras and c-myc oncogene expression interferes with morphological and functional differentiation of mammary epithelial cells in single and double transgenic mice.

We studied the effects of the tissue-specific and lactogenic hormone-dependent expression of the recombinant whey acidic protein (Wap)-ras and Wap-myc oncogenes on the differentiation of the mammary epithelium in transgenic mice. The histological appearance of mammary glands in pregnant, lactating, and postlactational animals and their ability to express milk protein genes were analyzed. Activated Ha-ras expression caused a decrease of milk protein synthesis during the lactation period. The formation of glandular epithelium and the postlactational regression of epithelial cells were not affected. c-myc expression impaired the development of the glandular epithelium, and milk protein synthesis was decreased strongly. Epithelial cell proliferation continued during lactation and postlactationally. Coexpression of both oncogenes in double transgenic mice synergistically affected differentiation and resulted in a high number of neoplastic foci. Palpable tumors were observed only after a latency of 3-4 months. Tumor cells utilize the Wap promoter hormone independently, express increased levels of Wap-ras and induce adjacent stromal cells to produce tenascin.