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Oncology Abstracts (2019) 1 P014 | DOI: 10.1530/oncolabs.1.P014

1Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires Argentina; 2Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, AHMS, University of Adelaide, Adelaide, SA 5005, Australia.

Overexpression of ErbB-2, a member of ErbB family of receptor tyrosine kinases, occurs in 15–20% of breast cancers (BC) and is considered a major oncogenic driver. Despite clinical efficiency of ErbB-2-targeted therapies (e.g. trastuzumab), resistance to said drugs is a major issue. While ErbB-2 is mainly a cell membrane-bound receptor, it can migrate to the nucleus (NErbB-2) where it acts as a transcription factor or coactivator. We revealed that NErbB-2 is a major proliferation driver in trastuzumab-resistant BC. Here, we used JIMT-1 BC cells, which constitutively express NErbB-2 and are intrinsically trastuzumab-resistant, to explore the transcriptional consequences of NErbB-2 activity. RNAseq was performed on JIMT-1 cells transfected with and without a human ErbB-2 nuclear localization domain mutant (hErbB-2ΔNLS), unable to translocate to the nucleus, which acts as a dominant negative inhibitor of endogenous NErbB-2 migration. Exclusion of ErbB-2 from the nucleus resulted in up-regulation of 280 genes and down-regulation of 33 genes. Functional analysis using String Database revealed that blockade of NErbB-2 presence increased expression of genes involved in type-I interferon and cytokine-mediated signaling pathways (FDR 7.52E-34 and 4.48E-32, respectively). Interferon beta (IFNβ) and lambda (IFNλ), key players in interferon signaling, were among top up-regulated genes. In independent validation experiments, blockade of NErbB-2 induced IFNβ and IFNλ mRNA expression in JIMT-1 and HCC-1569 trastuzumab-resistant cells. hErbB-2ΔNLS also induced TRIM22 and OAS-2 mRNA expression, two proteins activated by interferon signaling. JIMT-1 xenografts demonstrated that blockade of NErbB-2 localization by injection of hErbB-2ΔNLS significantly inhibits in vivo tumor growth. Interestingly, IFNβ and IFNλ mRNA levels were also up-regulated in hErbB-2ΔNLS-injected tumors. Moreover, treatment with IFNβ or IFNλ inhibited in vitro proliferation of JIMT-1 cells. Collectively, these findings reveal IFNβ and IFNλ as novel targets of NErbB-2 and suggest that NErbB-2 drives the growth of trastuzumab-resistant BC cells via transcriptional repression of interferons.

Volume 1

7th International Pacific Rim (PacRim) Breast and Prostate Cancer Meeting

17 Mar 2019 - 20 Mar 2019

PacRim Breast and Prostate Cancer Group 

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