The Role of the DNA Damage Response and Abnormal Cellular Divisions in Genetically Unstable Cells in Breast Cancer

Ongoing Research by the Bourke Group (Email: emer.bourke@nuigalway.ie )

BreastCancer is broadly classified into 4 subtypes: 2 estrogen receptor (ER)+ive (Luminal A and B) and 2 ER-ive groups (HER2, Basal-like (BL)). While effective receptor-targeted strategies have been developed for hormone receptor/HER2-positive tumours, basal-like tumours are notoriously difficult to treat as they lack specific hormone receptor or HER2 targets, most falling into the category of “triple-negative” breast cancers (TNBCs). They are associated with poor outcome as conventional chemotherapy is the sole mode of clinical management. Elucidation of the pathogenic mechanisms underlying the phenotypes is necessary to identify potential prognostic and therapeutic targets and improve the outlook in particular for the triple-negative subtype.

Genome integrity is maintained by DNA damage response pathways and the extent to which the DDR is active in tumour cells is a measure of the level of genomic instability. A sound mitotic apparatus is also required to preserve chromosome integrity during cell division and defects of the centrosome (the organelle responsible for organisation of cell division) are associated with genetically unstable cells. My previous research mainly focused on how DNA damage impacts on centrosome function via the DNA damage response pathways. DNA damage-induced centrosomal defects in turn promote further genomic instability and tumour progression.

Current research questions

1) Are the DNA damage response and centrosome function differently regulated across the subtypes of breast cancer? We test the hypothesis that the subtypes of breast cancer represent distinct biological entities possessing different hallmarks of genomic instability. Particularly, do triple-negative tumours, currently considered a disparate group, have a distinct pattern of molecular mechanisms involving DNA damage response and/or centrosome biology that may predict disease outcome and susceptibility to treatment?

2) Can the mechanisms of multipolar spindle formation be harnessed to drive tumour cells into programmed cell death? Increased centrosome number is a common characteristic of several human tumours. Centrosome amplification (>2 centrosomes per cell) is thought to be an active mechanism evolved by the cell to drive excessively damaged cells into a multidirectional cell division and death, thereby eliminating them. High grade invasive breast cancer strongly associates with high levels of centrosome amplification, yet significantly without the expected increase in multipolar divisions. Our current research investigates the mechanisms which allow tumour cells with multiple centrosomes to survive what should be a lethal condition. Targeted inhibition of such survival mechanisms driving breast cancer cells into multipolarity and cell death, would preferentially target tumour cells above normal cells for disease management.

These projects are in close collaboration with the Karolinska Institutet, the University of Gothenburg (Sweden), the Genome stability group (NUIG) and Prof Michael Kerin’s group (CSI). The work employs patient tissue microarrays (TMAs) from the large biobank of breast cancer tumours built here at UCHG from 1999-2014.

 

For a list of Dr. Emer Bourke’s publications, please click here:

http://www.nuigalway.ie/medicine-nursing-and-health-sciences/medicine/disciplines/pathology/stafflist/emerbourke/