The goals of this proposal are to investigate how the tumorigenic potential of specific oncogenes is affected by the developmental stage an endocrine status of the mammary gland. Specifically, this proposal will investigate the sensitivity of the mammary gland to oncogenic transformation at specific developmental states and under specific hormonal stimulation. This will he accomplished by developing a molecular switch system to regulate the expression of oncogenes in the mammary gland. The switch system will consist of a bitransgenic system in which the expression of the desired oncogene is under the control of a transgene that encodes a regulatable transcription factor. The transcription factor will be a genetically modified steroid hormone receptor that will not bind its natural ligand, but activated by exogenous compounds such as RU486. The target gene will be silent until the receptor is activated in response to a exogenous compound. The activated receptor will specifically induce the expression of the desired oncogene. By using this system the expected expression of oncogenes in the mammary gland can be closely regulated. This will allow an investigation into the susceptibility of the mammary gland to tumorigenesis at specific ages and endocrine status.
| Xu, J; Nawaz, Z; Tsai, S Y et al. (1996) The extreme C terminus of progesterone receptor contains a transcriptional repressor domain that functions through a putative corepressor. Proc Natl Acad Sci U S A 93:12195-9 |
