UBC Theses and Dissertations
Dissecting the function of Y-box binding protein-1 (YB-1) during the development of breast cancer Davies, Alastair Henry
The series of events that trigger the transformation of a normal cell into a malignant cell are unclear. One prospective driver of tumourigenesis is Y-box binding protein-1 (YB-1). BLG-YB-1 transgenic mice all form mammary tumours and the protein is expressed in over 40% of breast carcinomas. The studies presented in this thesis aimed to uncover the function of YB-1 during the transformation process. To this end, we conditionally expressed YB-1 in normal human mammary epithelial cells (HMECs). In agreement with tumours from the transgenic mice, genomic instability was manifested in the form of numerical and structural chromosomal abnormalities. To query the mechanism responsible for these phenotypes, we assessed global changes in signal transduction using an antibody microarray. Notably, we identified an increase in LIM kinase (LIMK1/2) activity that acted as a catalyst for cytokinesis failure. Subsequent cell cycle checkpoint slippage, due to cyclin E over-expression, potentiated centrosome amplification leading to mitotic spindle abnormalities. The resulting genomic instability was not stochastic but rather it increased susceptibility to cancer by promoting low-level HER2 amplification, as one example. Deeper interrogation revealed that YB-1 was capable of fully transforming HMECs. Through stabilization and upregulation of the histone acetyltransferase p300, YB-1 reprogrammed HMECs into stem/progenitor-like tumour-initiating cells (TICs). Mechanistically, the relaxation of promoter-centered chromatin permitted YB-1 to bind and transcriptionally regulate the TIC-associated genes BMI1, CD44, and CD49f. These cells formed DCIS-like luminal outgrowths in a three-dimensional model of breast acini. Over time, pressures exerted by YB-1 led to the emergence of cells expressing RSK2 and hTERT that had the capacity to form tumours in vivo. These cells were subtyped as triple-negative breast cancer (TNBC), a particularly aggressive form of the disease that is prone to relapse. We discovered that YB-1 regulates the multidrug resistance transporter ABCG2 to render the CD44⁺/CD49f⁺ TIC subpopulation refractory to traditional chemotherapy. However, these cells were responsive to RSK inhibitors, which prevent the activation of YB-1. As a whole, the studies outlined in this thesis indicate that YB-1 facilitates the genesis of TNBC through epigenetic reprogramming and targeting it has the potential to overcome drug resistance and prevent tumour recurrence.
Item Citations and Data
Attribution-NonCommercial-NoDerivatives 4.0 International