Based upon observations made under the auspices of our current NIH award (for which the application is submitted as a competitive renewal), we have formulated several new hypotheses which motivate the research contained in this application and in several other non-overlapping applications submitted to the NIH and other funding agencies whose review is currently pending. Specifically, our observations have led us to hypothesize that: Ovarian, endometrial, and breast carcinomas express very low levels of wild-type CSF-1R transcript and protein similar --if not identical -- to that expressed in macrophages, trophoblast and breast carcinoma cells, while ovarian carcinomas also express significantly higher levels of novel CSF-1R-like transcripts and proteins which may result from transcription and alternative splicing or from mutation or rearrangement of wild-type CSF-1R or other genomic sequences. To investigate this hypothesis, we propose: To fully characterize ovarian carcinoma CSF-1R-like transcripts, with special emphasis on the unusual CSF-1R transcript isoforms which we have recently observed in several ovarian carcinoma lines. To determine whether the locus from which these novel CSF-1R-like mRNAs are transcribed are mutated or rearranged, or whether they are novel alternative splice-products of an otherwise wild-type CSF-1R gene. To define the protein isoforms encoded by the novel CSF-1R-like transcripts and define how their biochemical and physiological functions relate to those of the wild-type CSF-1R protein. To define the expression of these novel CSF-1R-like transcripts and the proteins they encode in vivo relative to the wild-type CSF-1R in benign and neoplastic ovarian epithelial cell as well as the prognostic significance of their expression relative to the wild-type CSF-1R by the application of ISH and immunohistochemical techniques. The latter will require the development of poly- and monoclonal antibody reagents which can discriminate the novel CSF-1R receptor-like proteins from the wild-type and others which discriminate activated, tyrosine auto(tyrosine) phosphorylated (novel and wild-type) CSF-1Rs from the resting molecules.
| Sapi, E; Flick, M B; Gilmore-Hebert, M et al. (1995) Transcriptional regulation of the c-fms (CSF-1R) proto-oncogene in human breast carcinoma cells by glucocorticoids. Oncogene 10:529-42 |
