Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice.
OBJECTIVE
Bone is a common site for breast cancer metastasis. Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFR) are involved in the regulation of bone resorption. This study examined the effects of STI571 (imatinib mesylate), which inhibits PDGFR tyrosine kinase signaling, on the growth of human breast cancer cells in the bone of nude mice with consequent osteolysis.


METHODS
Human breast cancer MDA-MB-435 cells were injected into the tibia of female nude mice. Two weeks later the mice were treated with p.o. and injected water (control), daily p.o. STI571, weekly injection of paclitaxel, or daily STI571, plus weekly paclitaxel, for up to 8 weeks. Growth of tumors in bones and osteolysis were monitored by digital radiography and tumors were collected for histochemical analysis.


RESULTS
Mice treated with STI571 or STI571 plus paclitaxel had smaller bone tumors with less lytic bone destruction than did mice treated with water or paclitaxel alone. The results of treatment with paclitaxel plus STI571 did not differ from those with STI571 alone. Immunohistochemistry showed that PDGF-A, PDGF-B, PDGFRalpha, and PDGFRbeta were expressed in the bone tumors. STI571 treatment inhibited PDGFR phosphorylation in tumor cells and tumor-associated endothelial cells, coincident with increased apoptosis, reduced proliferation, and lower microvessel density in the tumors.


CONCLUSIONS
Activated PDGFRs are expressed by endothelial and tumor cells in breast cancer tumors growing in the bone of nude mice. Interfering with PDGFR signaling may be an approach to control the progressive growth of breast cancer cells and thus reduce bone lysis.
Lev
Dina Chelouche
DC
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
Kim
Sun Jin
SJ
Onn
Amir
A
Stone
Valerie
V
Nam
Do-Hyun
DH
Yazici
Sertac
S
Fidler
Isaiah J
IJ
Price
Janet E
JE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology; D011859:Radiography; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C075278:platelet-derived growth factor A; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D017239:Paclitaxel