Abstract LB-C09: Hematological and Neurological Expressed 1-Like (HN1L) is a Novel Therapeutic Target for Triple Negative Breast Cancer

Abstract

Abstract Background and Objective: Triple negative breast cancer (TNBC: ER-,PR-,Her2-), is characterized by its aggressive clinical behavior with high incidence of visceral metastasis to the lungs and brain. These patients do not respond to hormonal therapy and show intrinsic resistance to conventional chemotherapy. Robust evidence indicates that treatment-resistance and metastases may arise from a subpopulation of cells with tumor-initiating capacity called breast cancer stem cells (BCSC). We are one of the first groups to demonstrate that residual tumors after exposure to chemotherapy are enriched for BCSC (Li et. al, J Natl Cancer Inst 100:672-9, 2008). We have previously described a tumorigenic treatment-resistant gene signature of 493 genes derived from patient biopsies (Creighton et. al, Proc Natl Acad Sci USA 106:13820-5, 2009).This finding narrowed down the possible cancer stem cell growth related genes from genome wide to only 493 genes and provided candidate genes for screening potential targets that affect BCSC self-renewal. Further screening and re-evaluation of the candidate genes determined a previously unidentified cancer gene, Hematological and Neurological Expressed 1-Like (HN1L) as the target of cancer stem cell self-renewal. HN1L is known to be involved in embryo development, but has been remained as an orphan gene. Thus, the objective of this study was to investigate the role of HN1L in in TNBC and to validate HN1L as a novel therapeutic target. Results: We found from the TCGA database that the expression of HN1L is up-regulated in more than 20% breast cancer and is negatively correlated with relapse-free survival in TNBC patients. Silencing of HN1L considerably suppressed BCSC population in vitro and in vivo, sensitized tumors to chemotherapy in vivo, and substantially reduced lung metastasis. Mechanistically, our study identified HN1L as an novel and putative transcription factor regulating expression of STAT3 and the related regulatory genes including Leptin-receptor (Lepr) and miR-150. These upstream pathways converge to result in a persistent activation of a STAT3-regulated gene network promoting downstream BCSC self-renewal pathways. Correlatively, the TNBC patients exhibiting gene signature from HN1L knockdown tend to survive longer. Conclusion: we described here for the first time that HN1L is a novel therapeutic target for triple negative breast cancer. This study highlights the importance of targeting HN1L that deactivates STAT3 and abrogates its function in BCSC self-renewal. Further investigation of HN1L in TNBC-targeted therapies will offer new strategies to treat this aggressive disease. Citation Format: Dong Soon Choi, Liu Yi, Cristian Rodriguez-Aguayo, Bhuvanesh Dave, Stephen T.C. Wong, Anil K. Sood, Jenny C. Chang. Hematological and Neurological Expressed 1-Like (HN1L) is a Novel Therapeutic Target for Triple Negative Breast Cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C09.