Targeting breast cancer stem cells through their P-Rex1/Rac1 signalling

Breast cancer is the second most common cause of death from cancer in women in the UK. Although the conventional and targeted therapy options can increase the disease-free survival of patients, the acquired drug resistance and tumour relapse are frequently observed in clinics. At the core of this clinical problem are the breast cancer stem cells (Br-CSCs), a small fraction of tumour cells with stemness features and the capacity to re-initiate tumour formation. Br-CSCs are likely to be responsible for primary tumour formation, metastasis, acquired drug-resistance and tumour recurrence. We have determined that the activity of the small GTPase, Rac1, is essential for the self-renewal and maintenance of Br-CSCs. On the other hand, the loss-of-function of P-Rex1, an upstream regulator of Rac1 that is highly expressed in luminal breast tumours, results in the premature differentiation and thereby the depletion of Br-CSCs. Additionally, we have shown that the tumour-specific splice variant of Rac1, Rac1b, regulates the Br-CSC plasticity and its genetic deletion leads to a transition of Br-CSCs into the therapy-sensitive MET-CSC state. These results propose that P-Rex1 and Rac1b variant can serve as two attractive molecular targets for the elimination of Br-CSCs.
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Dr Heidi Welch
The Brian Heap Seminar Room