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Histopathology of Salivary and Mammary Gland Tumors in Transgenic Mice Expressing a Human Ha-ras Oncogene

Department of Tumor Biology, Schering-Plough Research, Bloomfield, New Jersey 07003 [L. L. N., C. M. D., M. G.], and Safety Evaluation Center, Schering-Plough Research, Lafayette, New Jersey 07848 [R. D. T.]

Mutated ras genes are powerful transforming agents in vitro and are found in a wide variety of human tumors in vivo. We characterized the histopathology and p21 protein expression associated with tumorigenesis in line 69 transgenic mice carrying an activated, human c-Ha-ras gene on the Y-chromosome (A. C. Andres, C. A. Schonenberger, B. Groner, L. Hennighausen, M. LeMeur, and P. Gerlinger, Proc. Natl. Acad. Sci. USA, 84: 1299–1303, 1987). Male mice developed salivary and/or mammary gland tumors. The salivary tumors were adenosquamous carcinomas arising from serous areas of the submandibular gland. They characteristically exhibited densely packed cords and sheets of moderately anaplastic cells. Tumorigenic tissue had a high mitotic index, and all tumor-bearing animals had an ongoing inflammatory response as evidenced by extensive immune cell infiltration of affected tissue. Half of the mammary gland tumors were adenosquamous carcinomas with multiple foci of squamous metaplasia, while the rest were adenocarcinomas containing glandular tissue. Most tumors had a high mitotic index, and abnormal mitotic figures were common. All tumors produced p21 ras, as confirmed by immunohistochemistry and Western blots. Both tumor types expressed elevated levels of p21 protein. Microscopic lung metastases were present in 5 of 35 animals (14%). Our results suggest that this transgenic mouse will provide a useful model for testing therapies directed against ras-associated tumorigenesis.

¹ To whom requests for reprints should be addressed, at B7-B-90, Department of Tumor Biology, 60 Orange St., Bloomfield, NJ 07003.

Received 2/ 7/91. Accepted 5/ 7/91.

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