The Impact of Tyrosine Kinase Signaling on Breast Cancer Development

In human breast cancers, c-Src is overexpressed in approx. 70 of cancers, suggesting that it interacts functionally with the HER family of receptors. In many human cancers, including breast cancer, EGFR is activated in an autocrine or paracrine manner by TGF alpha. To test whether interactions between TGF alpha, EGFR and c-Src result in synergistic increases in breast tumor development, transgenic mice expressing each of these genes under the control of the MMTV promoter are being developed. The MMTV promoter responds transcriptionally to glucocorticoids and steroids and causes expression of the transgene in steroid hormone responsive organs. We have generated MMTV EGFR mice and demonstrated the presence of the transgene by PCR and Southern analyses. At the present time, although we have evidence for elevated expression of the EGFR in hormonally responsive tissues especially in multiparous animals, only one of the EGFR transgenic mice that we have developed had a visible tumor however, 4 of 12 females showed focal hyperplasia of the mammary gland, 9 of 12 females showed varying degrees of cystic endometrial hyperplasia and dysplasia in the uterus or uterine horn and 6 of 12 females exhibited follicular or luteal cysts in ovary or oviducts and also exhibited a mild to moderate hypertrophy or dysplasia. Male reproductive tissues examined did not show any signs of preneoplastic conversion. The ability of TGF alpha to enhance tumor formation in MMTV EGFR transgenic mice was tested by crossing MMTV TGF alpha transgenic mice. Bigenic mice carrying both of these transgenes have been generated and are being examined for rates of tumor formation. It is expected that breast tumors will form in these bigenic mice, providing evidence for the role of both EGFR and TGF alpha in breast tumorigenesis. MMTV c-Src transgenic mice are under preparation, and the strategy and progress in generating such a strain will be discussed.