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UBC Theses and Dissertations

Y-box binding protein-1 induces MET, CD44, and CD49f thereby promoting the capacity for tumour initiation. To, Karen Ka-Yan

Abstract

Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where its expression correlates with enhanced tumour cell growth and drug resistance. YB-1 is also significantly associated with disease recurrence, suggesting links to tumour-initiating cells (TICs). We recently reported that YB-1 binds to the promoters of genes associated with a stem/progenitor-like phenotype through a chromatin immunoprecipitation (ChIP)-on-chip screen, including genes encoding the MET receptor, CD44, and CD49f. We first confirmed that YB-1 induces oncogene MET by activating its promoter. Further, both YB-1 and MET expression were detected in purified populations of primary human mammary progenitor cells. Similarly, we confirmed that YB-1 binds the gene promoters of reported TIC markers CD44 and the stem cell marker CD49f (α6 integrin) using conventional ChIP. Human breast TICs, reportedly CD44⁺/CD24⁻/low, self-renew, grow in mammospheres, and may evade current drug therapies, leading to increased relapse rates in patients. We observed that P-YB-1S102 co-localized to a CD44High breast cancer cell subpopulation with increased growth capacities. Silencing YB-1 down-regulated MET, CD44 and CD49f, while overexpression of wild-type (YB-1WT) or a constitutively activated form (YB-1S102D) increased MET, CD44 and CD49f transcripts and proteins. Consistent with these findings, the mammary glands of YB-1 transgenic mice had elevated CD44 and CD49f protein with associated hyperplasia. Moreover, the expression of YB-1S102D in SUM 149 cells, enhanced mammosphere formation and growth in soft agar. Conversely, silencing either CD44 or CD49f in these cells reversed YB-1S102D enhanced growth. Consistent with a role for TICs in relapse, Paclitaxel activated YB-1 and this correlated with induced CD44. Further, expression of YB-1WT enhanced mammosphere growth in the presence of Paclitaxel. Taken together, our data suggests that YB-1 induces MET, CD44, and CD49f expression which may be a part of the mechanism used to enhance tumour cell growth, disease relapse, and drug resistance.

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