Role of TGF-B1-Mediated Down Regulation of NF-kB/Rel Activity During Growth Arrest of Breast Cancer Cells

The NF-kBRel family of dimeric transcription factors has been shown to promote cell survival, and increasing evidence suggests involvement in carcinogenesis. Recently, NF-kBRel was found to be constitutively active in the nuclei of human breast cancer cell lines, as well as in 7,l2-dimethylbenzaanthracene 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-kBRel 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-kBRel and AhR may be critically involved in proliferation andor 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-kBRel, and c-Myc proteins in a common pathway towards malignant progression of mammary epithelial cells.