The Role of a LIM Only Factor, LMO-4, in Breast Cancer

LMO4 is a transcription factor which belongs to the LIM-only (LMO) gene family of oncogenes. We have now shown that expression of LMO4 is associated with undifferentiated cellular stage of breast epithelial cells, such as that found during lobuloalveolar development in pregnancy and in breast cancer. Yet, LMO4 is not induced by estrogen, suggesting that it may participate in an estrogen-independent pathway. Consistent with this idea, we found that LMO4 expression is induced by the Neu/ller2 oncogene in breast cancer cells, suggesting that LMO4 plays a role in this important oncogenic pathway. We created a transgenic mouse model to demonstrate that interfering with LMO4 results in significant inhibition of lobuloalveolar development, indicating 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. On a molecular level, we found that LMO4 functions by interacting with Clim transcriptional co-factors and is likely recruited to DNA in breast cancer cells by the DNA-binding protein GATA3. Expression profiling studies show that LMO4 and Clim regulate several genes involved in breast cancer carcinogenesis. In summary, our studies identify LMO4 as an important regulator of cell growth in normal mammary epithelial cells and in breast cancer cells.