Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity

Oncogenic activation of MYC occurs often in breast carcinoma and is associa ted with poor prognosis. Loss or inactivation of mechanisms that restrain M YC may therefore be involved in tumor progression. In this study, we show t hat the MYC-interacting adaptor protein BINI is frequently missing in malig nant breast cells and that this loss is functionally significant. BINI was expressed in normal and benign cells and tissues but was undetectable in 6/ 6 estrogen receptor-positive or estrogen receptor-negative carcinoma cell l ines examined. Similarly, complete or partial losses of BIN I were document ed in 30/50 (60%) cases of malignant breast tissue analyzed by immuno-histo chemistry or RT-PCR. Abnormalities in the organization of the BINI gene wer e apparent in only a minority of these cases, suggesting that most losses w ere due to epigenetic causes. Nevertheless, they were functionally signific ant because ectopic BINI induced programmed cell death in malignant cells l acking endogenous BINI but had no effect on the viability of benign cells. We propose that loss of BINI may contribute to breast cancer progression by eliminating a mechanism that restrains the ability of activated MYC to dri ve cell division inappropriately. (C) 2000 Wiley-Liss, Inc.