Loss of heterozygosity and tumor suppressor activity of BIN1 in prostate carcinoma

Abstract

The genetic events underlying the development of prostate cancer are poorly defined, c-Myc is often activated in tumors that have progressed to metastatic status, so events that promote this process may be important. Bin l is a nucleocytoplasmic adaptor protein with features of a tumor suppressor that was identified through its ability to interact with and inhibit malignant transformation by c-Myc. We investigated a role for Bin 1 loss or inactivation in prostate cancer because the human Bin 1 gene is located at chromosome 2q14 within a region that is frequently deleted in metastatic prostate cancer but where no tumor suppressor candidate has been located. A novel polymorphic microsatellite marker located within intron 5 of the human Bin 1 gene was used to demonstrate loss of heterozygosity and coding alteration in 40% of informative cases of prostate neoplasia examined. RNA and immunohistochemical analyses indicated that Bin 1 was expressed in most primary tumors, even at slightly elevated levels relative to benign tissues, but that it was frequently missing or inactivated by aberrant splicing in metastatic tumors and androgen-independent tumor cell lines. Ectopic expression of Bin 1 suppressed the growth of prostate cancer lines in vitro. Our findings support the candidacy of Bin 1 as the chromosome 2q prostate tumor suppressor gene. (C) 2000 Wiley-Liss, Inc.