Functional Analysis of LIM Domain Proteins and Co-Factors in Breast Cancer

摘要

We identified a novel transcription factor, LMO4, which is highly expressed in breast epithelial cells during mid- pregnancy when these cells are proliferating and invading the stroma. Since previous members of the LIM only (LMO) gene family are oncogenes, we hypothesized that LMO4 may play roles in mammary gland development and cancer. We have now shown that expression of LMO4 correlates with proliferation, and in transgenic mice we showed that dominant- negative LMO4 inhibits lobuloalveolar development, demonstrating that LMO4 plays roles in proliferation and/or invasion of breast epithelial cells. Because these cellular features are associated with breast carcinogenesis and because LMO4 is overexpressed in a subset of breast cancers, our studies implicate LMO4 as a possible oncogene in breast cancer. In addition, we found that the LMO4 gene is activated by the Her2/Neu receptor in breast cancer cells, providing further linkage to breast cancer. In biochemical assays we showed that LMO4 may act by associating with the GATA3 transcription factor, also expressed in mammary epithelial cells. We have also created stable breast cancer cell lines in which we can induce expression of LMO4 and Clim2. With this method, we have identified several target genes of LMO4, one of which is Bone Morphogenic Protein 7 (BMP-7), which can affect survival of breast cancer cells by regulating apoptosis. In summary, we have defined a role for a new gene, LMO4, in mammary epithelial cell proliferation in normal development and in breast cancer cells.