Negative regulation of estrogen receptor alpha transactivation functions by LIM domain only 4 protein.

LIM domain only 4 (LMO4), a member of the LIM-only family of transcriptional coregulatory proteins, consists of two LIM protein-protein interaction domains that enable it to function as a linker protein in multiprotein complexes. Here, we have identified estrogen receptor alpha (ERalpha) and its corepressor, metastasis tumor antigen 1 (MTA1), as two novel binding partners of LMO4. Interestingly, LMO4 exhibited binding with both ERalpha and MTA1 and existed as a complex with ERalpha, MTA1, and histone deacetylases (HDAC), implying that LMO4 was a component of the MTA1 corepressor complex. Consistent with this notion, LMO4 overexpression repressed ERalpha transactivation functions in an HDAC-dependent manner. Accordingly, silencing of endogenous LMO4 expression resulted in a significant increased recruitment of ERalpha to target gene chromatin, stimulation of ERalpha transactivation activity, and enhanced expression of ERalpha-regulated genes. These findings suggested that LMO4 was an integral part of the molecular machinery involved in the negative regulation of ERalpha transactivation function in breast cells. Because LMO4 is up-regulated in human breast cancers, repression of ERalpha transactivation functions by LMO4 might contribute to the process of breast cancer progression by allowing the development of ERalpha-negative phenotypes, leading to increased aggressiveness of breast cancer cells.