Functional and Molecular Characterisation of Breast Cancer Stem Cells

Breast cancer is one of the most common cancers worldwide, with over 2 million new cases in 2018. While some breast cancers in the early stages can be cured through surgery and chemotherapy, tumour progression and relapse are more challenging to treat and are responsible for poor prognosis. Therefore, understanding the basic mechanisms driving breast cancer progression and resistance to chemotherapy is imperative for developing new treatment strategies. Previous research has found that some tumour cells are more resistant to chemotherapy than others and some “chemoresistant” cells can regenerate the tumour even if only a few of them remain. These cells are known as cancer stem cells. The host laboratory previously identified a population of cancer stem cells that can initiate luminaltype mammary gland tumours in a mouse model of breast cancer. The cancer stem cells they identified are marked by a protein on their surface called Lgr6, which also exists in humans.The aim of this project was to use genetically engineered mouse models to separate out the tumour cells marked by Lgr6 from the rest of the tumour cells, and determine the molecular differences between the two populations using a technique called RNA sequencing. In conclusion, this project identified genes associated with cancer stem cell behaviour, which in the future might be targeted to inhibit breast cancer relapse.

Over two years, the project was divided into two main parts:
1) Firstly, cancer stem cells were isolated from the rest of the tumour cells in a genetically engineered mouse model of breast cancer and analysed to identify characteristic genes that could be responsible for their cancer stem cell behaviour;
2) Secondly, mouse tumour cells were grown in culture and the candidate “cancer stem cell genes” identified in part 1 were targeted one by one to see the effects on the cultured tumour cells.

Work from part 1 produced a detailed analysis of gene expression in cancer stem cells marked by Lgr6 in comparison with other tumour cells (giving a list of candidate “cancer stem cell genes”), which was exploited in part 2. Results from part 2 demonstrated that several of these candidate cancer stem cell genes are involved in resistance to the chemotherapy drug doxorubicin. Together, the project results are being explored in further research to determine which of these candidate genes are most important for chemoresistance, how they work, and whether targeting cancer stem cells can inhibit tumour relapse. The initial results have been
disseminated informally within the research community and will be formally published in a peer-reviewed scientific journal with open access to the public once the research has been completed.

As part of the project, several state-of-the-art research techniques relating to the isolation of cancer stem cells from mouse models of breast cancer and their growth and manipulation in culture were optimised. The results represent an important catalogue of genes potentially associated with cancer stem cell behaviour which can be explored in future research. The finding that targeting individual candidate genes can inhibit tumour cell resistance to doxorubicin provides a promising research avenue for future strategies to combat chemoresistance in breast cancer. Because of the high incidence of breast cancer in society and the immense challenge posed by chemoresistance and relapse, this research could provide an important societal benefit.

Periodic Reporting for period 1 - BRECASTEM (Functional and Molecular Characterisation of Breast Cancer Stem Cells)

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