TY - JOUR
T1 - Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer
AU - Johnsen, Steven A.
AU - Güngör, Cenap
AU - Prenzel, Tanja
AU - Riethdorf, Sabine
AU - Riethdorf, Lutz
AU - Taniguchi-Ishigaki, Naoko
AU - Rau, Thomas
AU - Tursun, Baris
AU - Furlow, John
AU - Sauter, Guido
AU - Scheffner, Martin
AU - Pantel, Klaus
AU - Gannon, Frank
AU - Bach, Ingolf
PY - 2009/1/1
Y1 - 2009/1/1
N2 - Mammary oncogenesis is profoundly influenced by signaling pathways controlled by estrogen receptor α (ERα). Although it is known that ERA 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 ERα cofactors that colocalize and interact with ERα in primary human breast tumors. We show that both cofactors associate with estrogen-responsive promoters and regulate the expression of endogenous ERα target genes in breast cancer cells. Surprisingly, our results indicate opposing functions of LIM cofactors for ERα and LIM-HDs: whereas CLIM enhances transcriptional activity of LIM-HDs, it inhibits transcriptional activation mediated by ERα on most target genes in vivo. In turn, the ubiquitin ligase RLIM inhibits transcriptional activity of LIM-HDs but enhances transcriptional activation of endogenous ERα 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 ERA during the development of human breast cancer.
AB - Mammary oncogenesis is profoundly influenced by signaling pathways controlled by estrogen receptor α (ERα). Although it is known that ERA 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 ERα cofactors that colocalize and interact with ERα in primary human breast tumors. We show that both cofactors associate with estrogen-responsive promoters and regulate the expression of endogenous ERα target genes in breast cancer cells. Surprisingly, our results indicate opposing functions of LIM cofactors for ERα and LIM-HDs: whereas CLIM enhances transcriptional activity of LIM-HDs, it inhibits transcriptional activation mediated by ERα on most target genes in vivo. In turn, the ubiquitin ligase RLIM inhibits transcriptional activity of LIM-HDs but enhances transcriptional activation of endogenous ERα 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 ERA during the development of human breast cancer.
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U2 - 10.1158/0008-5472.CAN-08-1630
DO - 10.1158/0008-5472.CAN-08-1630
M3 - Article
C2 - 19117995
AN - SCOPUS:58249102074
VL - 69
SP - 128
EP - 136
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 1
ER -