title: Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer.
abstract: 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.
authors.affiliation: Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany. sjohnse@gwdg.de
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.forename: Cenap
authors.initials: C
authors.lastname: Güngör
authors.forename: Tanja
authors.initials: T
authors.lastname: Prenzel
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.forename: Lutz
authors.initials: L
authors.lastname: Riethdorf
authors.forename: Naoko
authors.initials: N
authors.lastname: Taniguchi-Ishigaki
authors.forename: Thomas
authors.initials: T
authors.lastname: Rau
authors.forename: Baris
authors.initials: B
authors.lastname: Tursun
authors.forename: J David
authors.initials: JD
authors.lastname: Furlow
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Martin
authors.initials: M
authors.lastname: Scheffner
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Frank
authors.initials: F
authors.lastname: Gannon
authors.forename: Ingolf
authors.initials: I
authors.lastname: Bach
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D055511:CCN Intercellular Signaling Proteins; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D060588:LIM Domain Proteins; D053766:Presenilin-2 / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; C486312:LDB1 protein, human; C484572:LDB2 protein, human; D060588:LIM Domain Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D014157:Transcription Factors; C492370:RLIM protein, human; D044767:Ubiquitin-Protein Ligases; C533922:CTSD protein, human; D002402:Cathepsin D