There is an urgent need for new cancer therapies that target the genes which drive the initiation and progression of cancer.
Current Laboratory Members
Professor Tom Gonda: Dr Jim Gray, Dr Ping Ye, Dr Ping Zhang, Dr Liang Zhao, Dr Dubravka Skalamera, Ms Amy Purdon, Ms Crystal McGirr, Mr Diwakar Pattabiraman, Ms Yvette Drabsch, Mr Ben Wilson, Mr Max Ranall and Mr Andrew Courtney.
Dr Dennis Dowhan: Mr Matthew Harrison.
Dr Ali Naderi: Ms Ji Liu.
Dr Paul Leo.
The major goal of the Molecular Oncogenesis Group is to identify and characterise genes, particularly oncogenes, involved in leukaemia and breast cancer. We do this not only to increase our basic understanding of cancer, but importantly, because such genes represent logical targets for the development of new anti-cancer therapeutics.
One side of our research focuses on a few specific genes or gene types, including MYB, BEX2 and regulators of alternate splicing, and aims to translate our findings into novel approaches for cancer therapy. Our other major endeavour is the development and application of high-throughput function-based gene discovery.
Current Research Projects
Identification and Characterisation of MYB target genes
The MYB oncogene encodes a transcription factor (Myb) that plays an essential role in normal haemopoiesis. MYB is also necessary for the continued growth of most leukaemias, and indeed can cause or contribute to leukaemia initiation or progression in several species including humans. A major focus of our current work on MYB is to identify key target genes that contribute to Myb’s leukaemogenic activity. We have conducted a microarray screen to identify candidate target genes in a myeloid cell line transformed by a “switchable” form of Myb. As well as known targets, several novel candidates, including microRNAs, have been identified and are being further characterised.
Figure 1. ERMYB Cells grow continuously when MYB is active (left), but undergo terminal differentiation to granulocytes and macrophages when MYB is inactive (right)
Approaches to therapeutic targeting of MYB in leukaemia and other cancers
By studying the ability of a series of Myb mutants to block differentiation and allow continued proliferation of haemopoietic cells, we have identified critical interactions between Myb and other transcriptional co-regulators, including the coactivator CBP/p300. In collaboration with Associate Professor Mark Smythe (UQ Institute for Molecular Bioscience) we are now aiming to disrupt these interactions using small peptides, which may lead to the development of an anti-Myb drug. Moreover, we are exploring the ability of other anti-cancer agents to synergise with MYB inhibition in killing leukaemia and other cancer cells. Because of the widespread involvement of MYB in major human cancers, including acute leukaemias, breast and colon cancers, therapies targeting MYB potentially have very broad applicability.
Role of MYB in human breast cancer
MYB is expressed in 60-70% of all breast cancers, and its expression in these cancers is controlled by oestrogen and the oestrogen receptor (ER). We showed that in breast cancer cells, MYB expression is regulated by blocking elongation of newly-initiated transcripts. This block is mediated by a “stem-loop/poly dT” (SL-dT) motif in the first intron of the gene. We have now found that oestrogen overcomes the block and induces MYB expression by stimulating ER binding to a site adjacent to the SL-dT motif.
Moreover, using antisense and inducible shRNA knock-down approaches, we have shown that MYB expression is required for the proliferation of ER-positive breast cancer cells. Our studies have also shown that MYB appears to suppress differentiation of breast epithelial cells. These studies are being extended to in vivo models using transgenic mice, conditional knock-out mice and xenograft systems.
Figure 2. shRNA knockdown of MYB in ZR-75-1 cells.
Development and application of high-throughput retroviral expression cloning – the ARVEC initiative 
The ARVEC project, in collaboration with Associate Professor Brian Gabrielli, Dr Sean Grimmond (UQ Institute for Molecular Bioscience) and Associate Professor Simon Barry (University of Adelaide), aims to construct a lentiviral cDNA library representing the entire human genome, and establish a facility for automated generation and screening of the viral vectors in cell-based functional assays using a 96-well plate format. This will allow us to identify genes that can confer any dominant phenotype for which a suitable cell-based assay can be developed. Our focus within the Institute's cancer research will be on genes that regulate processes such as proliferation/cell-cycle progression, differentiation, apoptosis and anti-cancer drug resistance.
Currently we have established the robotics platform and high-content imaging system which will read out the functional assays. Production of lentivirus using our robotics platform has also been systematically optimised. Approximately 1400 cDNAs have been transferred into our expression vector to generate a small pilot library to use in preliminary screens.
Figure 3. ARVEC facility.
Professor Gonda is currently offering postgraduate projects in his laboratory. Click here for more information.
Dr Dennis Dowhan's Research
At the beginning of the human genome project, it was speculated that the human genome was comprised of about ~100,000 genes. We now know that there are only ~32,000 genes, roughly one third of the number that were originally thought to exist. The molecular coupling of transcription and pre-mRNA processing during gene expression is rapidly becoming an important mechanism for the regulation of pre-mRNA alternative splicing. Alternative pre-mRNA splicing is an important molecular process that allows for increased protein diversity from a set number of genes. Interestingly, many genes that play a role in various types of cancer and cell cycle regulation are alternatively or aberrantly spliced.
The overall goal of my research is to investigate transcriptional and pre-mRNA splicing mechanisms, identify cofactors that regulate transcription/pre-mRNA processing and elucidate how these cofactors relate to genes that are alternatively or aberrantly spliced in cancer.
Current projects include:
- Identification of RNA binding proteins that play a role in breast and prostate cancer initiation and progression.
- Investigation into the post-transcriptional modification of transcriptional cofactors and splicing proteins in the regulation of transcription and RNA processing in relation to cancer.
- The examination of several tumour suppressor genes and oncogenes that are regulated by both steroid/nuclear hormone receptor signalling and alternative splicing mechanisms.
Contact Dr Dennis Dowhan.
Dr Ali Naderi's Research
Study of NGF/BEX2/NF-кB pathway in breast cancer
We have identified BEX2 (Brain-Expressed-X-linked 2 gene) as a novel breast cancer-related gene (Naderi et al, 2007). BEX2 is over-expressed in about 15% of breast tumours and mediates the anti-apoptotic activity of Nerve Growth Factor through the activation of Nuclear Factor-кB. My group is currently studying the functional aspects of this pathway.
The cross-talk between ErbB2 and androgen receptor signalling pathways in molecular apocrine ER- breast cancer
Molecular apocrine breast cancer constitutes around one-third of estrogen receptor negative cases. We have recently established a functional cross-talk between AR and ErbB2 pathways in the molecular apocrine breast cancer (Naderi et al, 2008). We are currently working to further characterise this cross-talk and identify applications for our findings.
Contact Dr Ali Naderi.