Insulin-like growth factor binding protein-3 prevents retinoid receptor heterodimerization: implications for retinoic acid-sensitivity in human breast cancer cells
Insulin-like growth factor binding protein-3 (IGFBP-3) has both IGF-dependent and -independent effects on cell growth, which are frequently growth-inhibitory. Interestingly, the development of a more aggressive phenotype in breast cancer cells (BCCs) correlates positively with elevated expression of IGFBP-3 and is often associated with all-trans-retinoic acid (atRA)-resistance. IGFBP-3 was previously demonstrated to interact directly with retinoid X receptor (RXR). In this study we have shown that IGFBP-5 also interacts with RXR and that both IGFBPs interact with retinoic acid receptor (RAR). To investigate whether the presence of IGFBP-3 regulates breast cancer cell responsiveness to atRA, we immuno-neutralized the IGFBP-3 expressed by the atRA-resistant Hs578T and MDA-MB-231 BCCs (which express IGFBP-3 constitutively) and showed that they become more sensitive to the growth-inhibitory effects of atRA. Similarly, in Hs578T cells expressing a reporter gene under the control of an RAR response element (RARE), depletion of IGFBP-3 resulted in the induction of reporter gene expression in response to atRA. In investigating possible mechanisms for IGFBP-3 regulation of atRA-sensitivity, we found that IGFBP-3 blocked the formation of RAR:RXR heterodimers and disrupted the ligand-inducible receptor complex. Thus, IGFBP-3 has the potential to reduce the RARE-mediated transactivation of target genes and modulate the atRA-response in BCCs.
|Authors||Schedlich, L. J.;O'Han, M. K.;Leong, G. M.;Baxter, R. C. :|
|Publisher Name||BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14715249|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/1846|