One of every 11 American women will develop mammary cancer (MC) during her lifetime. While detection of localized disease can allow curative surgery, unfortunately, the majority of patients are diagnosed with already disseminated disease not curable by surgery alone. Patients with metastatic MC do respond to hormonal and/or chemotherapy, however, these responses are rarely curative. To develop more effective treatments for metastatic MC, new approaches may be required. Recent animal studies of MC has suggested such a new approach. This lead is based upon the observation that not all inbred strains of rat are equally susceptible to either spontaneous or chemical induction of MC. A large series of genetically pure inbred strains of female rats were compared for the relative susceptibility to dimethylbenzanthracene (DMBA) induced mammary carcinogenesis. The inbred Sprague-Dawley (SD) strain is the most susceptible developing about 3 MC/rat and the inbred Copenhagen (Cop) the least susceptible strain developing 0 MC/rat. This differential susceptibility is due to intrinsic differences in the mammary glands themselves and not to differences in the host systemic environment. When inbred SD and Cop rats are crossbred, the resultant F1 hybrid females are resistant to the development of MC like their Cop parent. Further breeding studies demonstrated that Mendelian inheritance of a single dominantly acting allele is responsible for the resistance of the Cop female to chemically induced MC. As part of these breeding experiments it was observed that MC would initially appear in the F1 hybrids but would then spontaneously regress and not reappear. This suggested that some factor inherited from the Cop genome was able to actively suppress the development and possibly the maintenance of the malignant state.
The Specific Aims of this proposal therefore are to: 1) determine the generality of supppression of the appearance and/or maintenance of MC induced by DMBA treatment in a variety of F1 hybrids produced by crossbreeding Cop with a series of inbred rat strains, other than SD, and 2) to test whether the malignancy of established MC derived from SD rats can be directly suppressed when these MC cells are fused with mammary gland cells from Cop rats to form intraspecies hybrids. If the malignant phenotype is indeed suppressible in the intraspecies hybrids, the long term goal will be to identify, at the molecular level, the mechanism for this suppressive ability.
| Ichikawa, T; Ichikawa, Y; Isaacs, J T (1992) Genetic factors and suppression of metastatic ability of v-Ha-ras-transfected rat mammary cancer cells. Proc Natl Acad Sci U S A 89:1607-10 |
| Isaacs, J T (1991) A mammary cancer suppressor gene and its site of action in the rat. Cancer Res 51:1591-5 |
| Ichikawa, T; Kyprianou, N; Isaacs, J T (1990) Genetic instability and the acquisition of metastatic ability by rat mammary cancer cells following v-H-ras oncogene transfection. Cancer Res 50:6349-57 |
| Kyprianou, N; Isaacs, J T (1990) Relationship between metastatic ability and H-ras oncogene expression in rat mammary cancer cells transfected with the v-H-ras oncogene. Cancer Res 50:1449-54 |
| Isaacs, J T (1988) Inheritance of a genetic factor from the Copenhagen rat and the suppression of chemically induced mammary adenocarcinogenesis. Cancer Res 48:2204-13 |
| Isaacs, J T (1986) Genetic control of resistance to chemically induced mammary adenocarcinogenesis in the rat. Cancer Res 46:3958-63 |
