TY - JOUR
T1 - Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells
AU - Pratap, Jitesh
AU - Wixted, John J.
AU - Gaur, Tripti
AU - Zaidi, Sayyed K.
AU - Dobson, Jason
AU - Gokul, Karthiga Devi
AU - Hussain, Sadiq
AU - Van Wijnen, Andre J.
AU - Stein, Janet L.
AU - Stein, Gary S.
AU - Lian, Jane B.
PY - 2008/10/1
Y1 - 2008/10/1
N2 - Runx2, required for bone formation, is ectopically expressed in breast cancer cells. To address the mechanism by which Runx2 contributes to the osteolytic disease induced by MDA-MB-231 cells, we investigated the effect of Runx2 on key components of the "vicious cycle" of transforming growth factor β (TGFβ)-mediated tumor growth and osteolysis. We find that Runx2 directly up-regulates Indian Hedgehog (IHH) and colocalizes with Gli2, a Hedgehog signaling molecule. These events further activate parathyroid hormone-related protein (PTHrP). Furthermore, Runx2 directly regulates the TGFβ-induced PTHrP levels. A subnuclear targeting deficient mutant Runx2, which disrupts TGFβ-induced Runx2-Smad interactions, failed to induce IHH and downstream events. In addition, Runx2 knockdown in MDA-MB-231 inhibited IHH and PTHrP expression in the presence of TGFβ. In vivo blockade of the Runx2-IHH pathway in MDA-MB-231 cells by Runx2 short hairpin RNA inhibition prevented the osteolytic disease. Thus, our studies define a novel role of Runx2 in upregulating the vicious cycle of metastatic bone disease, in addition to Runx2 regulation of genes related to progression of tumor metastasis.
AB - Runx2, required for bone formation, is ectopically expressed in breast cancer cells. To address the mechanism by which Runx2 contributes to the osteolytic disease induced by MDA-MB-231 cells, we investigated the effect of Runx2 on key components of the "vicious cycle" of transforming growth factor β (TGFβ)-mediated tumor growth and osteolysis. We find that Runx2 directly up-regulates Indian Hedgehog (IHH) and colocalizes with Gli2, a Hedgehog signaling molecule. These events further activate parathyroid hormone-related protein (PTHrP). Furthermore, Runx2 directly regulates the TGFβ-induced PTHrP levels. A subnuclear targeting deficient mutant Runx2, which disrupts TGFβ-induced Runx2-Smad interactions, failed to induce IHH and downstream events. In addition, Runx2 knockdown in MDA-MB-231 inhibited IHH and PTHrP expression in the presence of TGFβ. In vivo blockade of the Runx2-IHH pathway in MDA-MB-231 cells by Runx2 short hairpin RNA inhibition prevented the osteolytic disease. Thus, our studies define a novel role of Runx2 in upregulating the vicious cycle of metastatic bone disease, in addition to Runx2 regulation of genes related to progression of tumor metastasis.
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U2 - 10.1158/0008-5472.CAN-08-1078
DO - 10.1158/0008-5472.CAN-08-1078
M3 - Article
C2 - 18829534
AN - SCOPUS:54249097017
SN - 0008-5472
VL - 68
SP - 7795
EP - 7802
JO - Cancer research
JF - Cancer research
IS - 19
ER -