Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer
Authors
Johnsen, Steven A.Gungor, Cenap
Prenzel, Tanja
Riethdorf, Sabine
Riethdorf, Lutz
Taniguchi-Ishigaki, Naoko
Rau, Thomas
Tursun, Baris
Furlow, J. David
Sauter, Guido
Scheffner, Martin
Pantel, Klaus
Gannon, Frank
Bach, Ingolf
Document Type
Journal ArticlePublication Date
2009-01-02Keywords
Breast NeoplasmsCathepsin D
Cell Line, Tumor
Cell Nucleus
DNA-Binding Proteins
Estrogen Receptor alpha
Gene Expression Regulation, Neoplastic
Humans
Intercellular Signaling Peptides and Proteins
Presenilin-2
Receptors, Progesterone
Repressor Proteins
Response Elements
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Transcriptional Activation
Ubiquitination
Genetics and Genomics
Metadata
Show full item recordAbstract
Mammary oncogenesis is profoundly influenced by signaling pathways controlled by estrogen receptor alpha (ERalpha). Although it is known that ERalpha exerts its oncogenic effect by stimulating the proliferation of many human breast cancers through the activation of target genes, our knowledge of the underlying transcriptional mechanisms remains limited. Our published work has shown that the in vivo activity of LIM homeodomain transcription factors (LIM-HD) is critically regulated by cofactors of LIM-HD proteins (CLIM) and the ubiquitin ligase RING finger LIM domain-interacting protein (RLIM). Here, we identify CLIM and RLIM as novel ERalpha cofactors that colocalize and interact with ERalpha in primary human breast tumors. We show that both cofactors associate with estrogen-responsive promoters and regulate the expression of endogenous ERalpha target genes in breast cancer cells. Surprisingly, our results indicate opposing functions of LIM cofactors for ERalpha and LIM-HDs: whereas CLIM enhances transcriptional activity of LIM-HDs, it inhibits transcriptional activation mediated by ERalpha on most target genes in vivo. In turn, the ubiquitin ligase RLIM inhibits transcriptional activity of LIM-HDs but enhances transcriptional activation of endogenous ERalpha target genes. Results from a human breast cancer tissue microarray of 1,335 patients revealed a highly significant correlation of elevated CLIM levels to ER/progesterone receptor positivity and poor differentiation of tumors. Combined, these results indicate that LIM cofactors CLIM and RLIM regulate the biological activity of ERalpha during the development of human breast cancer.Source
Cancer Res. 2009 Jan 1;69(1):128-36. Link to article on publisher's siteDOI
10.1158/0008-5472.CAN-08-1630Permanent Link to this Item
http://hdl.handle.net/20.500.14038/44109PubMed ID
19117995Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-08-1630