Section of Experimental Oncology

Margaret Knowles

MOLECULAR BIOLOGY OF UROLOGICAL CANCER PROGRAMME

Professor of Experimental Cancer Research

m.a.knowles@leeds.ac.uk

Molecular Biology of Urological Cancers

Cancer of the bladder is the fifth most common cancer with over 11,000 new cases and almost 5,000 deaths from the disease each year in the U.K.

The aim of my research group is to identify key genes involved in the development of bladder cancer, to elucidate their function and to apply this information in the clinic. We study genome-wide DNA copy number changes and LOH by array-CGH and SNP array analysis and screen for mutations in specific genes to provide comprehensive genetic profiles of human cancers.

CGH studies have identified novel amplicons, one of which on 6p contains E2F3 a key cell cycle regulatory transcription factor. Functional studies confirm that E2F3 is the major target within this amplicon and we have shown that Rb inactivation is a necessary co-operating event in human bladder tumours (Figure 1).

We are studying several other genes in detail including FGFR3 which is mutated and over- expressed in many bladder tumours (Figure 2) and may represent a useful therapeutic target.

The PI3 kinase pathway genes PIK3CA, PTEN and TSC1 are also mutated leading to dysregulation of this pathway in many bladder tumours. We have generated telomerase-immortalised normal human ureteric urothelial cells for functional studies of candidate genes. These are being used to build an in vitro model of bladder cancer pathogenesis that recapitulates the genomic changes found in tumours.