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Regulation of Estrogen-Dependent Transcription by the LIM Cofactors CLIM and RLIM in Breast Cancer

¹ Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Göttingen, Germany; ² Program in Gene Function and Expression and ³ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; ⁴ Center for Molecular Neurobiology, ⁵ Institute for Tumor Biology, ⁶ Institute of Pharmacology, and ⁷ Institute of Pathology, University Medical Center Hamburg-Eppendorf; ⁸ Practice of Pathology, Hamburg, Germany; ⁹ European Molecular Biology Laboratory, Heidelberg, Germany; ¹⁰ Section of Neurobiology, Physiology and Behavior, University of California, Davis, California; and ¹¹ Department of Biology, University of Konstanz, Konstanz, Germany

Requests for reprints: Steven A. Johnsen, Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany. Phone: 49-551-39-10373; Fax: 49-551-39-13713; E-mail: sjohnse{at}gwdg.de or Ingolf Bach, University of Massachusetts Medical School, Worcester, MA. Phone: 508-856-5627; Fax: 508-856-4650; E-mail: Ingolf.Bach{at}umassmed.edu.

Key Words: Breast cancer • mammary gland • transcriptional regulation • cofactors • Estrogen • Estrogen receptor • LIM cofactors • CLIM • RLIM

Mammary oncogenesis is profoundly influenced by signaling pathways controlled by estrogen receptor (ER). Although it is known that ER 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 ER cofactors that colocalize and interact with ER in primary human breast tumors. We show that both cofactors associate with estrogen-responsive promoters and regulate the expression of endogenous ER target genes in breast cancer cells. Surprisingly, our results indicate opposing functions of LIM cofactors for ER and LIM-HDs: whereas CLIM enhances transcriptional activity of LIM-HDs, it inhibits transcriptional activation mediated by ER on most target genes in vivo. In turn, the ubiquitin ligase RLIM inhibits transcriptional activity of LIM-HDs but enhances transcriptional activation of endogenous ER 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 ER during the development of human breast cancer. [Cancer Res 2009;69(1):128–36]