Stathmin is involved in the cooperative effect of Zoledronic acid and gefitinib on bone homing breast cancer cells in vitro

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.