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


Project Description

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.

The candidate should have an academic scientific training, culminating in an M.Sc in a relevant subject (e.g. molecular/cellular/cancer biology). Previous experience in working with animal models or primary cell cultures would be preferable.

Applicants that have UK or EU citizenship can be considered for the fully funded Research Impact scholarships (RIS) if their formal applications will be received latest by April 4th, 2019. For more information on RIS please check:

Applicants that have non-UK or non-EU citizenships should confirm that they have potential self-funding prior to application.

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit

References

• Olabi S., Ucar A., Brennan K., Streuli CH. Integrin-Rac signalling for mammary epithelial stem cell self-renewal. Breast Cancer Res. 2018
• Ucar A., Streuli CH. A role for β-3 integrins in linking breast development and cancer. Developmental Cell. 2014
• Acar A., Simoes BM., Clarke RB., Brennan K. A role for Notch signalling in breast cancer and endocrine resistance. Stem Cells Int. 2016.
• Moreno-Layseca P., Ucar A., Sun H., Wood A., Olabi S., Gilmore AP., Brennan K., Streuli CH. The requirement of integrins for breast epithelial proliferation. Eur J Biol, 2017-08-31
• Marei H., Malliri A. GEFS: Dual regulation of Rac1 signalling. Small GTPases, 2017

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