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J. Biol. Chem., Vol. 281, Issue 21, 14563-14572, May 26, 2006

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Parathyroid Hormone-related Protein Regulates Tumor-relevant Genes in Breast Cancer Cells^*

Angela Dittmer, Martina Vetter¹, Dario Schunke¹, Paul N. Span, Fred Sweep, Christoph Thomssen, and Jürgen Dittmer²

From the Klinik für Gynäkologie, Universität Halle, Ernst-Grube-Strasse 40, 06120 Halle, Germany and the Department of Chemical Endocrinology, Radboud University Nijmegen Medical Centre, NL-6500 HB Nijmegen, The Netherlands

The effect of endogenous parathyroid hormone-related protein (PTHrP) on gene expression in breast cancer cells was studied. We suppressed PTHrP expression in MDA-MB-231 cells by RNA interference and analyzed changes in gene expression by microarray analysis. More than 200 genes showed altered expression in response to a PTHrP-specific small interfering (si) RNA (siPTHrP). Cell cycle-regulating gene CDC2 and genes (CDC25B and Tome-1) that control CDC2 activity showed increased expression in the presence of siPTHrP. CDC2 activity was also found to be higher in siPTHrP-treated cells. Studies with PTHrP peptides 1–34 and 67–86, forskolin, and a PTH1 receptor (PTH1R)-specific siRNA showed that PTHrP regulates CDC2 and CDC25B, at least in part, via PTH1R in a cAMP-independent manner. Other siPTHrP-responsive genes included integrin 6 (ITGA6), KISS-1, and PAI-1. When combined, siRNAs against ITGA6, PAI-1, and KISS-1 could mimic the negative effect of siPTHrP on migration, whereas siKISS-1 and siPTHrP similarly reduced the proliferative activity of the cells. Comparative expression analyses with 50 primary breast carcinomas revealed that the RNA level of ITGA6 correlates with that of PTHrP, and higher CDC2 and CDC25B values are found at low PTHrP expression. Our data suggest that PTHrP has a profound effect on gene expression in breast cancer cells and, as a consequence, contributes to the regulation of important cellular activities, such as migration and proliferation.

Received for publication, September 26, 2005 , and in revised form, March 17, 2006.

^* This work was supported by Bundesministerium für Bildung und Forschung Grant NBL3 FKZ 6/07. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Klinik für Gynäkologie, Universität Halle, Ernst-Grube-Str. 40, 06120 Halle, Germany. Tel.: 49-345-557-1338; Fax: 49-345-557-5261; E-mail: juergen.dittmer{at}medizin.uni-halle.de.

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