BAMBI is overexpressed in ovarian cancer and co-translocates with Smads into the nucleus upon TGF-ß treatment

Abstract

Transforming growth factor beta (TGF-beta) signaling via Smads plays a central role in carcinogenesis. Bmp and activin membrane-bound inhibitor (BAMBI) was initially described as a pseudoreceptor antagonizing TGF-beta receptor activation, thus impairing signaling. Here we wanted to estimate the role of BAMBI in ovarian cancer. The function of BAMBI was studied using a cell line model and intracellular localization experiments. The impact of BAMBI expression on patient outcome was estimated by real-time PCR and immunohistochemistry. We demonstrate for the first time a nuclear co-translocation of BAMBI with Smad2/3 upon TGF-beta treatment. Moreover, overexpression of BAMBI in an in vitro model led to significantly increased proliferation (doubling time -37.0%, P=0.010), migration (+581.2%, P=0.004) and resistance to TGF-beta-mediated apoptosis (decrease of apoptosis from 30% in the control cells to 7% in the BAMBI-overexpressing cells). Although-prima facie-this fits to the thesis of BAMBI as a pseudoreceptor, it may also be explained by modulation of TGF-beta signaling in the nucleus, leading to the observed pro-oncogenic properties. The tumor promoting impact of BAMBI mRNA overexpression in vitro could not be confirmed in primary tumor samples, and while nearly all tumor samples showed up-regulation of BAMBI (37.3% 1+, 39.2% 2+, and 16.7% 3+, respectively) compared to undetectable BAMBI in healthy pre- and post-menopausal ovarian epithelia, no impact of BAMBI expression on recurrence free and overall survival could be observed. These findings provide new insights into the Smad-mediated pathway by inferring that BAMBI is a novel modulator of TGF-beta signaling. Copyright (c) 2010 Elsevier Inc. All rights reserved.