Osteoblast-conditioned medium promotes proliferation and sensitizes breast cancer cells to imatinib treatment.
Inhibition of platelet-derived growth factor receptor (PDGFR) signaling restricts the growth of human breast cancer in the bone of nude mice. We hypothesized that osteoblast-secreted substances may alter the response capacity of breast cancer cells to the PDGFRs tyrosine kinase inhibitor imatinib mesylate. We found that osteoblast-conditioned medium (OCM) increases the proliferation rate of the estrogen receptor negative (ER-) MDA-MB-231 and of the ER+ MCF-7 human breast cancer cell lines and the growth-promoting effect on ER+ cells is independent from estrogen. OCM significantly improved the dose- and the time-dependent sensitivity of the tumor cells to the anti-proliferative effect of imatinib. We also found that MDA-MB-231 and MCF-7 cells express the two PDGFRs subtypes, PDGFR-alpha and PDGFR-beta, and OCM treatment increases the expression of the PDGFRs. Furthermore, imatinib inhibited the phosphorylation rate of its target tyrosine kinase receptors. We conclude that bone microenvironment, through osteoblast-secreted substances may cause estrogen-independent proliferation of breast cancer cells by a mechanism mediated by the induction of PDGFRs expression. The enhanced sensitivity of OCM-treated breast cancer cells to imatinib would justify investigation on the efficacy of imatinib in bone breast cancer metastasis.
Brama
Marina
M
Department of Medical Physiopathology, University of Rome La Sapienza, Rome, Italy.
Basciani
Sabrina
S
Cherubini
Sara
S
Mariani
Stefania
S
Migliaccio
Silvia
S
Arizzi
Mario
M
Rosano
Giuseppe
G
Spera
Giovanni
G
Gnessi
Lucio
L
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D006801:Humans; D000068877:Imatinib Mesylate; D010006:Osteoblasts; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis* / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
D000970:Antineoplastic Agents; D001549:Benzamides; D017077:Culture Media, Conditioned; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta