Bin1: a favorable prognostic marker and chemotherapeutic modulator in neuroblastoma

A35 Bin1 protein displays multiple functions such as suppression of oncogenic transformation and promoting apoptosis. Loss or reduction of Bin1 expression has been evident in many human cancers including breast, prostate, and neuroblastoma (NB), and correlated with the poor outcome of patients. NB originates from precursor cells of the peripheral nervous system and is the most common extracranial solid tumor in children. The tumor is metastatic in 70% of NB patients at the time of diagnosis and the overall prognosis is particularly poor despite aggressive therapies (10-40% survival in high-risk cases). Here we show that Bin1 is frequently reduced or lost in cell lines derived from the bone marrow metastasis or abdominal mass of NB patients. To establish the direct functional link between Bin1 expression and NB, we created NB cell lines that stably overexpress Bin1. Because Bin1 has a role in apoptosis and because survival of cancer cells in the systemic circulation plays a crucial role in the multistep metastatic process, we examined the role of Bin1 in cell survival under an anchorage disrupted condition. Forced Bin1 overexpression in the stable cells increased cell death when cultured in Poly-Hema coated plates. This type of cell death is believed to be a specialized apoptosis (anoikis) . Additionally, many chemotherapeutic agents kill tumor cells via apoptosis, and we also evaluated the influence of Bin1 on chemosensitivity. The results showed that Bin1 overexpression enhances cell killing by Doxorubicin, a commonly used anticancer agent. Proteomic analyses of cell lysates from Bin1 transfectants versus the vector controls revealed differentially expressed proteins. This indicates that Bin1 may modify the metastatic behaviors and chemoresponsiveness in NB via regulating the expression levels of other cellular proteins. Our results establish Bin1 as an important factor for NB metastasis and chemosensitivity. Thus, loss of Bin1 could serve as a prognostic marker for metastatic potential and therapeutic response, and targeting Bin1 and Bin1-regulated pathways could be a rational strategy for the treatment of high-risk NB patients.