Reduced expression of insulin like growth factor-2 mRNA binding protein 2 (IMP2) elevates TAZ via IMP3 in triple-negative breast cancer

Abstract

Insulin like growth factor-2 mRNA binding proteins IMP2 and IMP3 are usually expressed in aggressive triple-negative breast cancer (TNBC). Although, IMP3 plays a pro-tumorigenic role in breast tumors, function of IMP2 is less clear. Therefore, the objective of this study is to understand the functions of IMP2 in breast cancer. Using published mRNA and proteomic databases, we show that expressions of IMP2 and IMP3 correlate well in breast tumors. One of the important mechanisms by which IMP3 contributes to TNBC progression is its ability to activate TAZ oncoprotein via LATS1 and WNT5B. Surprisingly, short hairpin RNA (shRNA) mediated depletion of IMP2 protein increased TAZ and WNT5B expression in TNBC cells. We also noticed a decrease in phospho-LATS1. This observation is surprising because both IMP2 and IMP3 proteins are structurally very similar and are expressed together in TNBC. Moreover, we discovered that IMP2 depletion increased IMP3 expression which in turn enhanced TAZ and WNT5B level. Although both IMP2 & IMP3 interacts physically as evident from the co-immunoprecipitation experiment, the mechanism behind this reciprocal regulation is not clear at this point. Further, our analysis of a proteomic database identified proteins (notably SOX10, S100A9, SLC7A5 and ARG1) that are significantly elevated in TNBCs that express relatively higher IMP2 (IMP2^high) compared to IMP2^low tumors. Despite a strong positive correlation with IMP2, expressions of these genes are also increased in IMP2-depleted cells. Importantly, these genes are associated with poor patients survival. In conclusion, IMP2 seems to play a tumor suppressive role in TNBC cells.