PacRim7 7th PacRim Meeting Poster Presentations (1) (52 abstracts)
Nuclear ErbB-2 activity modulates the interferon signaling pathway in breast cancer cells resistant to anti-ErbB-2 therapies
Rosalía I Cordo Russo 1 , Santiago Madera 1 , María F Chervo 1 , Esmaeil Ebrahimie 2 , Luke Selth 2 , Violeta A Chiauzzi 1 , Zoya Kikhtyak 2 , Cecilia J Proietti 1 , Roxana Schillaci 1 , Eduardo H Charreau 2 , Theresa E Hickey 2 , Wayne D Tilley 2 & Patricia V Elizalde 1
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.
Article tools
My recent searches
My recently viewed abstracts
Authors
Oncology Abstracts
ISSN 2631-4657 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more