Zoledronic acid (Zol) is the most potent inhibitor of
bone resorption among the
bisphosphonates and is commonly used for inhibiting bone
metastasis. However, it remains unclear whether Zol provides a survival benefit. Recent findings indicate that
epidermal growth factor (
EGF) signaling is an important mediator of bone
metastasis. Thus, we examined the combined effects of Zol and an
EGF receptor-
tyrosine kinase inhibitor,
gefitinib, on the proliferation and invasion of a bone-seeking clone and the
breast cancer cell line MDA-MB-231. Combined treatment with Zol and
gefitinib synergistically inhibited both invasion and cell proliferation of the bone-seeking clone, but not those of the MDA-MB-231 cells. Two-dimensional difference gel electrophoresis and mass spectrometry demonstrated that
stathmin was down-regulated during these cooperative effects.
Stathmin is a signal transduction regulatory factor which plays an important role in cell division and malignant
tumor development. Our data suggest that
stathmin may be a promising target molecule for blocking bone
metastasis of
breast cancer.