Hong Xu - Research Home Page [Molecular Oncology and Breast Cancer Program : BC Cancer Research Centre]

Molecular Oncology and Breast Cancer Program

Hong Xu

hxu@bccancer.bc.ca

Department:	Molecular Oncology and Breast Cancer Program (@ the BCCRC since 2007)
Research Role:	Postdoctoral Fellow
Advisor:	Sam Aparicio
Education:	PhD (Medical Genetics / Yeast Genetics), University of Toronto, Canada, 2007 MSc (Membrane Biophysics), Chinese Academy of Sciences, China, 1998 BSc (Biochemistry), Beijing Normal University, China, 1992
Phone:	604-675-8000 ext.7557
Fax:	604-675-8218

Research Interests:

The role of BRCA2 in breast cancer

DNA repair pathways in breast cancer

High content siRNA screens

Around 8% of breast cancers are caused by inherited mutations in genes called BRCA1 and BRCA2 (BReast CAncer 1 and 2). Once the BRCA genes were identified in patients with inherited breast cancer, it became obvious that they are also mutated in many non-inherited, or sporadic, cancers. Understanding the function of the BRCA genes in normal and tumour cells is therefore an important problem in breast cancer research.

BRCA2 is a tumor suppressor gene that prevents abnormal cell growth and division by repairing damaged DNA. However, we do not fully understand how BRCA2 mutation contributes to breast cancer. We do know that genes usually carry out their functions through interactions with other genes. Genes responsible for different steps of the same process are organised into a pathway. Cells often use two or more different pathways to respond to the same stimulus. For example, there are multiple pathways that repair damaged DNA; one involves BRCA2, while a gene called PARP1 is involved in other pathways.

Ironically, the DNA repair defect that makes BRCA2-mutated cells cancerous also makes them easier to kill. Radiation and chemotherapy cause a massive amount of DNA damage that most normal cells can survive, but that is lethal to cells with defective DNA repair. However, it can be difficult to kill BRCA2-mutated cells if the intact PARP1-dependent repair pathways compensate for the missing BRCA2 pathway. Better results can be achieved if the other pathways are also disabled. Molecules that inhibit the PARP1 gene are currently undergoing clinical trials at various centres, including the BC Cancer Agency.

My research aims to identify interactions between the BRCA2 and PARP1 DNA repair pathways, and thus to increase the effectiveness of cancer treatment. I will use a new high throughput method that can determine the effects of repressing every single human gene, individually and in pairs. Genes that are in the same pathway have similar effects when repressed, and disabling two genes in the same pathway will have a similar effect to repressing any single gene. In contrast, disabling two genes belonging to different pathways will cause a more severe effect than repressing either gene alone. It is therefore possible to determine whether two genes are in the same or different pathways.

My lab is using this screening method to study genetic interactions in BRCA2-mutated cells. I will follow up on these results to identify genes in the BRCA2 or parallel pathways. I will also screen for gene mutations that make normal and BRCA2-mutated breast cells more sensitive to PARP1 inhibitors. Breast cancers with these gene mutations can potentially be treated using a lower dose of PARP1 inhibitor, with fewer side effects. In contrast, cancer cells with gene mutations that make them more resistant to PARP1 inhibition will require higher doses of PARP1 inhibitor for effective treatment. This sensitivity screen will also identify other mutations that sensitize cells to PARP inhibition, and may extend the application of PARP inhibitors to other tumors that do not contain BRCA2 mutations. I will also compare the results of the BRCA2 genetic interaction screen and the PARP1 inhibitor screen to acquire more information about the relationship between the BRCA2 and PARP1 pathways.

My project will enhance our understanding of the roles of BRCA2 and PARP1, and accelerate the development of new individually tailored therapeutic treatments for breast cancer.