Parathyroid hormone-related protein regulates tumor-relevant genes in breast cancer cells.
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 alpha6 (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.
Klinik für Gynäkologie, Universität Halle, Ernst-Grube-Strasse 40, 06120 Halle, Germany.
Angela
A
Dittmer
Martina
M
Vetter
Dario
D
Schunke
Paul N
PN
Span
Fred
F
Sweep
Christoph
C
Thomssen
Jürgen
J
Dittmer
D001706:Biopsy; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005576:Colforsin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039503:Integrin alpha6 / Q000378:metabolism; D059648:Kisspeptins; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D039503:Integrin alpha6; C106628:KISS1 protein, human; D059648:Kisspeptins; D044162:Parathyroid Hormone-Related Protein; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D005576:Colforsin