Abstract 2243: Alterations in the binding of Meis proteins to HoxB13 or to DNA promote prostate cancer progression

Abstract

Abstract Intro: One of the first germline mutations shown to confer an increased risk of early-onset prostate cancer (PrCa) is found in the Meis-binding domain of Homeobox B13 (HoxB13). Neither the function of this mutation nor the role of Meis proteins in PrCa has been elucidated. Meis proteins normally function as Hox gene cofactors, and regulate proliferation and cell fate. We hypothesize that disruption in normal Meis binding, either to transcriptional cofactors or DNA elements, is sufficient to alter gene transcription and increase progression of PrCa. Methods: Meis1/2 expression was used to stratify outcomes of men with Gleason 6/7 tumors in a retrospective bioinformatics analysis. Meis1/2 mRNA expression in cell lines was determined by qRT-PCR, and isoform distribution determined by TA-TOPO cloning. Cell number over time was determined for lines stably overexpressing Meis2E or A as compared to GFP in LNCaP and CWR-22Rv1. Results: We found that men diagnosed with intermediate Gleason scores and low expression of Meis had a worse prognosis than men with high levels of Meis. We found lower Meis mRNA expression in PrCa cell lines as compared to normal prostate epithelial cells. We determined that a variety of Meis2 isoforms are expressed in both cancer and normal, and the aggressive PrCa cell line CWR22Rv1 had a higher level of Meis2 isoforms with abrogated DNA-binding homeodomains. LNCaP cells overexpressing Meis2A showed significantly lower cell number over five days than GFP or Meis2E expressing cells. Conclusions: Full length Meis proteins may act as tumor suppressors while the homeodomain-less isoforms may act as oncogenes in the context of PrCa. This is innovative because we are the first to look at the role of Meis proteins in PrCa, and significant because it's linked to evidence involving mutations in HoxB13. Citation Format: Hannah J. Brechka, Masis Isikbay, Raj Bhanvadia, Donald Vander Griend. Alterations in the binding of Meis proteins to HoxB13 or to DNA promote prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2243. doi:10.1158/1538-7445.AM2015-2243