Postgraduate research opportunities Targeting the Nuclear Import Pathway as a Treatment for Triple Negative Breast Cancer

Breast cancer is the most commonly-diagnosed cancer, and a leading cause of female cancer-associated mortality. Though breast cancer survival has been substantially improved by hormone therapies, patients lacking hormone receptors experience limited therapeutic options and a poor survival outcome. Recent analyses have identified aberrant over-expression of nuclear import machinery (i.e. Karyopherins) as a biomarker of breast cancer aggressiveness. Under homeostatic conditions, the Karyopherin transporter family regulate protein subcellular localization and function which is essential for signal transduction, DNA repair, cellular proliferation and survival. In cancer, aberrant KPNA2 activity leads to pathogenic protein mislocalisation that coupled to tumour mutational burden, gives rise to a highly-invasive tumour phenotype.

This project will consider studying the in vitro effects of Karyopherin depletion on DNA damage repair, cell cycle phase progression, phenotype and survival in a panel of DNA repair proficient and deficient breast cancer cell lines. A combination of metabolomics and quantitative immunofluorescence will be used to track phenotypic changes of baseline and transformed cell models. Triple-negative and aggressive breast cancers are commonly characterized by mutations in DNA repair factors, so in vitro combination effects of Karyopherin depletion and DNA damage repair inhibition on DNA repair and cellular survival will also be investigated. It is anticipated that Karyopherin depletion will lead to loss of cell viability, cellular senescence, and a less-invasive in vitro phenotype.

Knowledge of the association between aberrant Karyopherin over-expression and an aggressive tumour phenotype in parallel to tumour mutational burden offers the scope for discovery of novel drugs, biomarkers and synthetically-lethal synergistic drug combinations.

Techniques used

• Metabolomics
• Molecular Biology
• Data analysis
• Cell culture