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Negative Regulation of Estrogen Receptor Transactivation Functions by LIM Domain Only 4 Protein

¹ Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center and ² Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

Requests for reprints: Rakesh Kumar, Department of Molecular and Cellular Oncology, Box 108, 1515 Holcombe Boulevard, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030. E-mail: rkumar{at}mdanderson.org.

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

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