Abstract 2249: N- and C-terminal peptides of the tumor suppressor protein IGFBP7 differentially induce growth arrest or senescence in breast cancer cells

Abstract

Abstract N- and C-terminal peptides of the tumor suppressor protein IGFBP7 differentially induce growth arrest or senescence in breast cancer cells Tania Benatar, Yutaka Amemiya, Valentina Evdokimova, Wenyi Yang and Arun Seth We have previously shown that insulin-like growth factor binding protein 7 (IGFBP7) is a tumor suppressor in breast cancer. IGFBP7 treatment resulted in breast cancer cell growth inhibition via induction of senescence and apoptotic pathways. Xenografted tumors overexpressing IGFBP7 were significantly growth-impaired as were the xenografted tumors treated systemically with purified IGFBP7. Given its low toxicity and high selectivity towards cancerous tissues, IGFBP7 is considered to be a promising anticancer agent. Its anticancer efficacy was further strengthened by our recent findings showing that the N-terminal 97 amino acid IGFBP7 domain is required for blocking Insulin-like Growth Factor 1 Receptor (IGF1R) activity and downstream PI3K-AKT-mTOR signaling. To further identify parameters that could predict IGFBP7-responsiveness in breast tumors, a variety of breast cancer cell lines were examined for growth responses and signaling pathways in response to IGFBP7 treatment. In this study, we found that treatment of some aggressive breast cancer cell lines, with IGFBP7 resulted in its proteolytic cleavage between Lys-97 and Ala-98 thus creating N-terminal and C-terminal specific peptides. While both the N- and C-terminal peptides were capable of growth inhibition, only the C-terminal fragment was efficient at inducing cellular senescence. The IGFBP7-responsiveness of breast cancer cell lines was a direct consequence of their ability to process IGFBP7. In order to compare which genes and pathways arewere affected by IGFBP7-full length (FL) versus cleaved form (CF) overexpression, we performed transcriptome Next- Generation sequencing from parental MDA-MB-468, MDA-MB-468 overexpressing full length (FL) of IGFBP7-FL or overexpressing cleaved form (CF) of IGFBP7-CF. We obtained 2486 gene differences for FL expressers and 3953 differences for CF expressers using mapped reads with a quality of 10 and at least a two-fold change. Of the thirteen breast cancer-associated genes that were differentially expressed between MDA-MB-468 cells and FL or CF expressing cells, most (10/13) were further enhanced upon IGFBP7-CF overexpression. Taken together, Tthese results indicate that IGFBP7s distinct N- and C-terminal functional domains, are ideal candidates for the development of companion theranostiitcs, as the ability of the tumor to effectively cleave IGFBP7 will determine efficacy of treatment. Citation Format: Tania C. Benatar, Yutaka Amemiya, Valentina Evdokimova, Wenyi Yang, Arun Seth. N- and C-terminal peptides of the tumor suppressor protein IGFBP7 differentially induce growth arrest or senescence in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2249. doi:10.1158/1538-7445.AM2014-2249