BMP‐6 over‐expression in prostate cancer is associated with increased Id‐1 protein and a more invasive phenotype

S Darby, SS Cross, NJ Brown, FC Hamdy… - The Journal of …, 2008 - Wiley Online Library
S Darby, SS Cross, NJ Brown, FC Hamdy, CN Robson
The Journal of pathology, 2008Wiley Online Library
Abstract Bone morphogenetic protein‐6 (BMP‐6) has been strongly implicated in prostate
cancer development and bone metastasis. Our previous data showed that BMP‐6 mRNA
was absent in patients with benign prostatic hyperplasia, but evident in primary tumours with
established secondary skeletal metastases. To examine the role of BMP‐6 in prostate
cancer progression, we have developed a BMP‐6‐regulatable, doxycycline‐inducible gene
expression system. BMP‐6 induction by doxycycline addition led to increased levels of BMP …
Abstract
Bone morphogenetic protein‐6 (BMP‐6) has been strongly implicated in prostate cancer development and bone metastasis. Our previous data showed that BMP‐6 mRNA was absent in patients with benign prostatic hyperplasia, but evident in primary tumours with established secondary skeletal metastases. To examine the role of BMP‐6 in prostate cancer progression, we have developed a BMP‐6‐regulatable, doxycycline‐inducible gene expression system. BMP‐6 induction by doxycycline addition led to increased levels of BMP‐6 RNA and protein, associated with nuclear translocation of SMADs and activation of the downstream target gene Id‐1. BMP‐6 protein did not enhance the proliferation rate of PC3M cells but did significantly increase the rate of migration and invasion in both PC3M and DU145 cells. Increased metalloproteinase (MMP‐1 and MMP‐9) mRNA levels were also observed following BMP‐6 induction. Luciferase reporter assays confirmed BMP‐6‐mediated activation of MMP‐1 and MMP‐9 promoters, indicating direct transcriptional activation of MMPs by BMP‐6. BMP‐6 stimulation also led to an increase in phosphorylation levels of MAPK proteins. We next examined the effects of BMP‐6 on the downstream gene Id‐1 in a cohort of prostate cancer patients. A tissue microarray (TMA) was constructed and samples stained for BMP‐6 and Id‐1 expression. We observed a significant increase in the intensity of staining of epithelial BMP‐6 in the cancer cases compared to the benign cases (Mann–Whitney U test, p < 0.0005) and in the intensity of staining of epithelial Id‐1 in the cancer cases compared to the benign cases (Mann–Whitney U test, p = 0.015). We further observed a significant positive correlation between epithelial staining for Id‐1 and BMP‐6 (p = 0.001) across all samples for both benign and cancer cases. These data demonstrate that BMP‐6 promotes migration and invasion of prostate cancer cells, potentially through activation of Id‐1 and MMP activation. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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