Targeting the MTA 1s-LM04 Pathway in Hormone Resistance

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 A (ERA) and its corepressor, metastasis tumor antigen 1 (MTA1), as two novel binding partners of LMO4. Interestingly, LMO4 exhibited binding with both ERA and MTA1 and existed as a complex with ERA, MTA1, and histone deacetylases (HDAC), implying that LMO4 was a component of the MTA1 corepressor complex. Consistent with this notion, LMO4 overexpression repressed ERA transactivation functions in an HDAC-dependent manner. Accordingly, silencing of endogenous LMO4 expression resulted in a significant increased recruitment of ERA to target gene chromatin, stimulation of ERA transactivation activity, and enhanced expression of ERA-regulated genes. These findings suggested that LMO4 was an integral part of the molecular machinery involved in the negative regulation of ERA transactivation function in breast cells. Because LMO4 is up-regulated in human breast cancers, repression of ERA transactivation functions by LMO4 might contribute to the process of breast cancer progression by allowing the development of ERA-negative phenotypes, leading to increased aggressiveness of breast cancer cells. (Cancer Res 2005; 65(22): 10594-601)