Journal article
EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours
Oncogene, Vol.37(30), pp.4073-4093
07/2018
DOI: 10.1038/s41388-018-0228-x
PMCID: PMC6062499
PMID: 29700392
Abstract
Triple-negative breast cancer (TNBC) tumours that lack expression of oestrogen, and progesterone receptors, and do not overexpress the HER2 receptor represent the most aggressive breast cancer subtype, which is characterised by the resistance to therapy in frequently relapsing tumours and a high rate of patient mortality. This is likely due to the resistance of slowly proliferating tumour-initiating cells (TICs), and understanding molecular mechanisms that control TICs behaviour is crucial for the development of effective therapeutic approaches. Here, we present our novel findings, indicating that an intrinsically catalytically inactive member of the Eph group of receptor tyrosine kinases, EPHB6, partially suppresses the epithelial-mesenchymal transition in TNBC cells, while also promoting expansion of TICs. Our work reveals that EPHB6 interacts with the GRB2 adapter protein and that its effect on enhancing cell proliferation is mediated by the activation of the RAS-ERK pathway, which allows it to elevate the expression of the TIC-related transcription factor, OCT4. Consistent with this, suppression of either ERK or OCT4 activities blocks EPHB6-induced pro-proliferative responses. In line with its ability to trigger propagation of TICs, EPHB6 accelerates tumour growth, potentiates tumour initiation and increases TIC populations in xenograft models of TNBC. Remarkably, EPHB6 also suppresses tumour drug resistance to DNA-damaging therapy, probably by forcing TICs into a more proliferative, drug-sensitive state. In agreement, patients with higher EPHB6 expression in their tumours have a better chance for recurrence-free survival. These observations describe an entirely new mechanism that governs TNBC and suggest that it may be beneficial to enhance EPHB6 action concurrent with applying a conventional DNA-damaging treatment, as it would decrease drug resistance and improve tumour elimination.
Details
- Title: Subtitle
- EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours
- Creators
- Behzad M Toosi - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaAmr El Zawily - Faculty of Science, Damanhour University, Damanhour, 22516, EgyptLuke Truitt - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaMatthew Shannon - Department of Computer Science, University of Saskatchewan, 176 Thorvaldsen Bldg., 110 Science Place, Saskatoon, SK, S7N 5C9, CanadaOdette Allonby - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaMohan Babu - Department of Chemistry and Biochemistry, Faculty of Science, University of Regina, Room 232, Research and Innovation Centre, Regina, SK, S4S 0A2, CanadaJohn DeCoteau - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaDarrell Mousseau - Cell Signaling Laboratory, Department of Psychiatry, College of Medicine, University of Saskatchewan, GB41 Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, CanadaMohsin Ali - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaTanya Freywald - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaAmanda Gall - Department of Biochemistry, College of Medicine, University of Saskatchewan, Room 2D01 Health Science Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, CanadaFrederick S Vizeacoumar - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaMorgan W Kirzinger - Department of Computer Science, University of Saskatchewan, 176 Thorvaldsen Bldg., 110 Science Place, Saskatoon, SK, S7N 5C9, CanadaC Ronald Geyer - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, CanadaDeborah H Anderson - Saskatchewan Cancer Agency, University of Saskatchewan, 4D30.2 Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, CanadaTaeHyung Kim - Donnelly Centre for Cellular and Biomolecular Research and Department of Computer Science, University of Toronto, Toronto, ON, M5S 3E1, CanadaAlana L Welm - Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USAPeter Siegel - Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, H3A 1A3, CanadaFranco J Vizeacoumar - Saskatchewan Cancer Agency, University of Saskatchewan, 4D30.2 Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, CanadaAnthony Kusalik - Department of Computer Science, University of Saskatchewan, 176 Thorvaldsen Bldg., 110 Science Place, Saskatoon, SK, S7N 5C9, Canada. kusalik@cs.usask.caAndrew Freywald - Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Room 2841, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK, S7N 0W8, Canada. andrew.freywald@usask.ca
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.37(30), pp.4073-4093
- DOI
- 10.1038/s41388-018-0228-x
- PMID
- 29700392
- PMCID
- PMC6062499
- NLM abbreviation
- Oncogene
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Language
- English
- Date published
- 07/2018
- Academic Unit
- Biology
- Record Identifier
- 9984217422202771
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