Negative regulation of estrogen receptor α 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 (ER alpha) and its corepressor, metastasis tumor antigen 1 (MTA1), as two novel binding partners of LMO4. Interestingly, LMO4 exhibited binding with both ER alpha and MTA1 and existed as a complex with ER alpha, MTA1, and historic deacetylases (HDAC), implying that LMO4 was a component of the MTA1 corepressor complex. Consistent with this notion, LMO4 overexpression repressed ER alpha transactivation functions in an HDAC-dependent manner. Accordingly, silencing of endogenous LMO4 expression resulted in a significant increased recruitment of ER alpha to target gene chromatin, stimulation of ER alpha transactivation activity, and enhanced expression of ER alpha-regulated genes. These findings suggested that LMO4 was an integral part of the molecular machinery involved in the negative regulation of ER alpha transactivation function in breast cells. Because LMO4 is up-regulated in human breast cancers, repression of ER alpha transactivation functions by LMO4 might contribute to the process of breast cancer progression by allowing the development of ER alpha-negative phenotypes, leading to increased aggressiveness of breast cancer cells.