The incidence of breast cancer in women in the Western world is of an order of one in ten and the mortality is still high. The need for improvement of therapy and prevention is, therefore, imminent. While the risk factors have been identified and the role of hormones clearly demonstrated, the etiology remains unknown. Enhanced expression of c-erb-B-2 protooncogene has been identified in about 30% of breast cancers and has been shown to be associated with poor prognosis. This tyrosine kinase receptor can be activated by estrogen and thus, it could provide a pathway for stimulation of estrogen negative tumors, some of which respond to the estrogen antagonist, tamoxifen. One of us have established recently that overexpression of pl85/ c-erb-B-2 receptor in human mammary epithelial cells inhibits transcription of E-cadherin and alpha-2 integrin subunit. Since reduced expression of the E-cadherin and integrin molecules has been found in less differentiated tumors and is associated with the increase invasiveness of breast cancer cells, this observation suggests that c-erb- B-2-mediated inhibition of expression of adhesion molecules could be involved in the initiation of the metastatic process. In the proposed study, we wish to investigate the signal transduction pathways and alteration in genes expression in human luminal epithelial cells, in which expression and function of c-erb-B-2 gene can be regulated and related to the expression of an particular gene. The study has four aims:
Aim #1, Estrogen as a ligand for c-erb-B-2 receptors in human mammary epithelial cells (HUXE);
Aim #2, Identification of signal pathway(s) mediated by c-erb-B-2 in HUME cells;
Aim #3, Identification of genes whose expression is affected in HUME cells by signals generated by a functional c-erb-B-2 receptor;
and Aim #4, Analysis of the promoters of c-erb-B-2 regulated genes. Finally, the expression of the newly identified, c-erb-B-2 regulated cDNAs, will be analyzed in primary breast carcinomas that has been already analyzed for c-erb-B-2 expression. The results of these studies should provide a new insight into our understanding of the molecular mechanisms by which c-erb-B-2 alters gene expression in mammary epithelial cells from which breast cancers develops. In addition, the identification of genes that are affected by c-erb-B-2 may provide new targets for therapeutic strategies.
| Lu, P J; Sundquist, K; Baeckstrom, D et al. (1999) A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer. J Biol Chem 274:15633-45 |
| Alford, D; Baeckstrom, D; Geyp, M et al. (1998) Integrin-matrix interactions affect the form of the structures developing from human mammary epithelial cells in collagen or fibrin gels. J Cell Sci 111 ( Pt 4):521-32 |
| Ye, J; Xu, R H; Taylor-Papadimitriou, J et al. (1996) Sp1 binding plays a critical role in Erb-B2- and v-ras-mediated downregulation of alpha2-integrin expression in human mammary epithelial cells. Mol Cell Biol 16:6178-89 |
| Graff, J R; Herman, J G; Lapidus, R G et al. (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55:5195-9 |
