Role of TGF-B1-Mediated Down Regulation of NF-kB/Rel Activity During Growth Arrest of Breast Cancer Cells
Abstract
The NF-kB/Rel family of dimeric transcription factors has been shown to promote cell survival, and increasing evidence suggests involvement in carcinogenesis. Recently, NF-kB/Rel was found to be constitutively active in the nuclei of human breast cancer cell lines, as well as in 7,l2-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors from Sprague-Dawley rats (S-D). Malignantly transformed human mammary epithelial cells (HMEC), derived by carcinogen treatment of non-tumorigenic parental MCF-l OF cells displayed increased constitutive NF-kB activation. In premalignant HMECs immortalized by carcinogen treatment in vitro, NF-kB activity was dysregulated in quiescence. Six founder lines of transgenic mice with targeted ectopic expression of the c-Rel subunit in the mammary gland were established, and studies are in progress to directly test the role of NF-kB/Rel in the mammary gland. Of note one of the mice has developed a mammary tumor. AhR and RelA cooperatively transactivated the c-myc promoter in the MCF-lOF HMECs, as well as in the Hs578T breast cancer cells. In the MCF- 1 OF cells AtIR and RelA cooperatively led to increased expression of the c-Myc nrotein. These results suggest that the activation of NF-kB/Rel and AhR may be critically involved in proliferation and/or malignant transformation of the mammary gland and its functional target may be the c-myc proto-oncogene. Overall, these studies provide evidence for involvment of the AhR, NF-kB/Rel, and c-Myc proteins in a common pathway towards malignant progression of mammary epithelial cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2000
- Accession Number
- ADA389354
Entities
People
- Dong Kim
Organizations
- Boston University