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Y-box binding protein-1 is essential for the growth and survival of HER2 over-expressing breast cancers and mediates trastuzumab resistance by inducing CD44

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Title: Y-box binding protein-1 is essential for the growth and survival of HER2 over-expressing breast cancers and mediates trastuzumab resistance by inducing CD44
Author: Dhillon, Jaspreet
Degree Master of Science - MSc
Program Experimental Medicine
Copyright Date: 2010
Publicly Available in cIRcle 2010-05-03
Abstract: Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in 40% of all subtypes of invasive breast carcinomas, where its expression is correlated with relapse and poor survival. HER2 amplifications are a frequent genetic abnormality observed in approximately 25% of breast cancers where its over-expression is associated with poor clinical outcome and decreased disease free survival. We recently reported that HER2 over-expressing breast cancers are dependent on YB-1 for growth and survival. In HER2 positive tumours we implicated YB-1 in sustaining cancer cells by its involvement in the STAT3 signalling pathway. The development of trastuzumab, a targeted therapy against HER2, has provided substantial advances in the care and treatment of patients whose tumours over-express HER2. Unfortunately, the development of acquired resistance to trastuzumab remains a prevalent challenge in the treatment of patients whose tumours express HER2. Since YB-1 is also linked to drug resistance in other types of cancer, we addressed its possible role in trastuzumab insensitivity. Employing an in vivo model of acquired resistance, we demonstrated that resistant cell lines have elevated levels of P-YB-1S¹°² and its activating kinase P-RSK and that these levels are sustained following trastuzumab treatment. Further, to demonstrate the importance of YB-1 in mediating drug resistance, the expression of the active mutant YB-1S¹°²D rendered the BT474 cell line insensitive to trastuzumab. Questioning the role of tumour initiating cells (TICs) and their ability to escape cancer therapies, we investigated YB-1’s involvement in inducing the cancer stem cell marker CD44. Notably, the resistant cells expressed more CD44 mRNA and protein compared to BT474 cells, which correlated with increased mammosphere formation. Expression of YB-1S¹°²D in the BT474 cells increased CD44 protein levels, resulting in enhanced mammosphere formation. Further, exposing BT474 cells to trastuzumab selected for a resistant subpopulation enriched for CD44. Conversely, siRNA inhibition of CD44 restored trastuzumab sensitivity in the resistant cell lines. Our findings provide insight on a novel mechanism employed by tumour cells to acquire the ability to escape the effects of trastuzumab and suggest that targeting YB-1 may overcome resistance by eliminating the unresponsive TIC population, rendering the cancer sensitive to therapy.
URI: http://hdl.handle.net/2429/24372
Scholarly Level: Graduate

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