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Role of Y-box binding protein-1 (YB-1) in breast cancer

University of British Columbia

The Y-box binding protein-1 (YB-1) is a multifunctional protein with roles in transcription, translation, DNA repair, and a recently identified function as an extracellular mitogen. YB-1 is over-expressed in various malignancies including breast carcinoma. Previous work from our laboratory has shown that YB-1 is expressed in approximately 40% of invasive breast carcinomas, and its expression correlates with relapse and poor survival. Further, the oncogenic potential of YB-1 has been demonstrated in breast cancer. In the studies presented in this thesis, we sought to understand the contribution of YB-1 as an oncogenic transcription factor to breast cancer. We focused our studies on the basal-like breast carcinoma (BLBC) and the human epidermal growth factor receptor 2 (HER2) over-expressing breast cancers, as patients with these subtypes suffer the worst prognosis. Using BLBC cell lines, we demonstrated that YB-1 induces expression of MET and PIK3CA to promote anchorage-independent growth and invasion respectively. These studies further identified YB-1 as a potential therapeutic target in BLBC. We then directed our focus to the HER2 over-expressing breast cancers. Although the development of trastuzumab (Herceptin®), a targeted therapy against HER2, has provided a substantial advance in the care of affected patients, resistance remains a prevailing challenge. We identified a novel mechanism by which signalling proteins, mitogen activated protein kinase interacting kinase (MNK) and p90 ribosomal S6 kinase (RSK), interact to increase phosphorylation of YB-1. In turn, phosphorylation of YB-1 promotes its nuclear translocation where it regulates transcription of genes involved in trastuzumab resistance. These results further suggest YB-1 as a therapeutic target to improve outcome for women with trastuzumab refractory disease. As a whole, the studies outlined in this thesis have contributed to our understanding of breast cancer pathogenesis and have identified novel aspects of YB-1 function in BLBC and in HER2 over-expressing breast carcinomas.

Text

2011-08-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/36668

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/