Characterizing the in vivo functions of P-Rex1 in breast development and tumourigenesis

Breast cancer is the most common cancer in the UK with a lifetime risk of 1-in-8 for women and accounts for 12,000 deaths annually. Although current treatment options can significantly reduce the tumour burden in breast cancer patients, tumour relapse is a frequently occurring problem. At the core of this clinical problem are the breast cancer stem cells (Br-CSCs), a small fraction of cells within tumours that have stem cell features. Br-CSCs are responsible not only for primary tumour formation, but also for metastasis, therapy resistance and tumour recurrence. Therefore, a true cure for breast cancer can only be achieved by developing novel therapies that can eradicate the tumour completely by eliminating Br-CSCs.

Our work suggests that we may be able to therapeutically target Br-CSCs by disrupting P-Rex1 function. P-Rex1 is a Guanine Nucleotide Exchange Factor (GEF) responsible for the activation of Rac1-GTPase downstream of PI3K and G-protein signalling pathways. We have discovered that P-Rex1 regulates the stemness of Br-CSCs found within human breast cancer cells. Now, we want to know whether P-Rex1 is required for tumour formation and metastasis in vivo. For this, we will use a mouse model of breast cancer and eliminate P-Rex1 function in the tumour cells of this model.

However if we want to target P-Rex1 therapeutically, we need to know whether it has any vital functions in normal tissues. Treating with a drug will obviously disrupt P-Rex1 function not only in the tumour, but also throughout the body. Consequently, the second half of the project will determine the function of P-Rex1 during normal development, particularly mammary gland development, by studying the phenotypes of P-Rex1-knockout mice.

Together, these studies will determine whether P-Rex1 is a promising molecular target for future therapies to eliminate Br-CSCs, and thereby provide a true cure for luminal breast tumours.

All the methodologies for the successful accomplishment of this project are present in the groups of the Supervisory team. The Ucar Lab will provide training in whole-mount analyses, stem cell culture, flow cytometry, and transplantation approaches. The Brennan Lab will provide the training on histological analyses and the determination of the molecular mechanisms. The Maliri Lab will provide training in mechanistic analyses of the signalling pathways.


http://www.breastcentre.manchester.ac.uk/Research-Groups/Ahmet-Ucar

http://www.breastcentre.manchester.ac.uk/Research-Groups/Keith-Brennan

https://www.cruk.manchester.ac.uk/Our-Research/Cell-Signalling