Characterisation of the Rac guanine nucleotide exchange factor, P-Rex1, and its interplay with type II inositol polyphosphate 4-phosphatase in breast cancer

Phosphoinositide 3-kinase (PI3K) signalling is aberrantly activated in many human cancers, including breast cancer. PI3K is activated downstream of receptor tyrosine kinases (RTKs) to generate the lipid second messengers, PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂, which activate numerous downstream signalling effectors including Akt and Rac-GEFs to promote cell proliferation, survival and motility. P-Rex1 (PtdIns(3,4,5)P₃-dependent Rac exchanger factor 1), a Rac-GEF, is highly expressed in a significant proportion of human breast cancers,and P-Rex1 overexpression may be oncogenic. In breast cancer cells, P-Rex1 promotes oncogenic signalling by integrating signals from HER2/3 and CXCR4 membrane surface receptors, however, P-Rex1 downstream signalling effectors are poorly characterised. This thesis examines the downstream effectors of P-Rex1 in breast cancer. Overexpression of P-Rex1 in ER-negative human breast cancer MDA-MB-231-luc-D3H1 cells enhanced oncogenic EGF-stimulated ERK1/2 activation, anchorage-independent cell growth, cell proliferation, migration, survival and xenograft tumour growth. In addition, PRex1 knockdown studies in ER-positive MCF-7-luc-F5 breast cancer cells supported the contention that P-Rex1 enhances oncogenic signalling in breast cancer via ERK1/2. In conclusion, studies presented in this thesis suggest that P-Rex1 is an important regulator of oncogenic ERK1/2 signalling in breast cancer.