Study of the role of KIFC1 in centrosome amplified breast cancer and its validation as a drug target

Triple-negative breast cancers are defined by a lack of oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. They are associated with poor prognosis and lack targeted therapies due to the absence of suitable molecular targets. Tumour addiction genes can make suitable molecular targets as cancer cells can become addicted to the expression of tumour addiction genes and the activity of their proteins to deal with the additional stresses that are collateral to the tumorigenic process. One of the additional stresses that malignant cells commonly have to survive through is the phenomenon of centrosome amplification. In order to survive in the presence of centrosome amplification, cancer cells upregulate the expression of the kinesin KIFC1. The work presented in this thesis characterised the role of KIFC1 as a malignant cell selective tumour addiction gene in breast cancer cell line models in-vitro and in-vivo using multiple RNAi techniques. The addiction of cancer cells to KIFC1 was revealed to be due to its requirement for the generation and maintenance of a bipolar mitotic spindle in centrosome amplified cells. These cells can display multipolar mitosis in the absence of the KIFC1 dependent clustering mechanism which can produce more than two inviable progeny. Moreover, using pericentrin immunohistochemistry staining on routinely collected formalin-fixed paraffin-embedded tissue, a potential patient stratification centrosome abnormality biomarker has been developed. This biomarker assay demonstrated its ability to predict the effect of KIFC1 targeting on cell population growth in breast cancer cell line models. Finally, this study revealed evidence that drug induced centrosome amplification can result in increased sensitivity to KIFC1 depletion in combination with Cisplatin, CP-466722 (ATM inhibitor), Oxamflatin (HDAC inhibitor), PD0325901 (MEK1/2 inhibitor), and Selumetinib (MEK1 inhibitor). Overall, the work from this thesis validated KIFC1 as a potential therapeutic target for centrosome amplified breast cancers either alone or in combination with centrosome amplification inducing compounds and developed a potential patient stratification biomarker to identify tumours with inherent centrosome amplification