Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer

Steven A. Johnsen, Cenap Güngör, Tanja Prenzel, Sabine Riethdorf, Lutz Riethdorf, Naoko Taniguchi-Ishigaki, Thomas Rau, Baris Tursun, John Furlow, Guido Sauter, Martin Scheffner, Klaus Pantel, Frank Gannon, Ingolf Bach

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)128-136
Number of pages9
JournalCancer Research
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Johnsen, S. A., Güngör, C., Prenzel, T., Riethdorf, S., Riethdorf, L., Taniguchi-Ishigaki, N., Rau, T., Tursun, B., Furlow, J., Sauter, G., Scheffner, M., Pantel, K., Gannon, F., & Bach, I. (2009). Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Research, 69(1), 128-136. https://doi.org/10.1158/0008-5472.CAN-08-1630