TGFbeta is a potent inhibitor of cell growth. TGFbeta elicits its effects on cells by activation of specific cell surface ser/thr kinase receptors. The TGFbeta Receptor Type (TbetaRII) is an essential part of the TGFbeta signaling pathway. Recent histochemical studies reveal of loss of (TbetaRII) expression in invasive breast cancer. We have shown that the early passage breast adenocarcinoma cell line MCF-7 cells are TGFbeta sensitive and non-tumorigenic. Late passage MCF-7 cells have lost their ability to express this important signaling component of negative autocrine regulation. These cells are insensitive to TGFbeta's effects on growth and are tumorigenic in athymic nude mice. Our experiments indicate that naturally occurring differences in the level of TbetaRII expression can lead to differences in tumorigenetic potential. We show that the expression of (TbetaRII) in the MCF-7 late passage cells is repressed at the level of transcription due to inadequate levels of the Sp1 transcription factor. Therefore, these cells represent an ideal model system for examining a non-mutational mechanism of re-expression of this important tumor suppressor activity. These studies may enable the identification of targets for manipulation of (TbetaRII) expression, which could lead to development of agents for prevention as well as treatment of breast cancer.
The specific aims of this project are: 1. Determine the mechanism responsible for the differential levels of Sp1 in MCF-7L and MCF-7E cells. 2. Determine the role of AP1 or CRE in TbetaRII expression in MCF-7E versus MCF-7L cells. 3. Determine the specificity of the action of Sp1 on the TbetaRII promoter compared to other Sp1 responsive genes.
| Sterling, Julie A; Wu, Liang; Banerji, Sunandita S (2006) PARP regulates TGF-beta receptor type II expression in estrogen receptor-positive breast cancer cell lines. Anticancer Res 26:1893-901 |
| Liu, Y; Zhong, X; Li, W et al. (2000) The role of Sp1 in the differential expression of transforming growth factor-beta receptor type II in human breast adenocarcinoma MCF-7 cells. J Biol Chem 275:12231-6 |
