Targeting IL-1 signalling in Notch-driven breast cancer

Abstract

The Notch signalling pathway is aberrantly activated in breast cancer, and is correlated with the triple negative subtype, therapy resistance and poor prognosis. Current treatment options are especially limited for triple negative cancers and patients presenting with resistance to conventional therapies. Inhibition of Notch signalling is an attractive therapeutic approach for these patients, however pan Notch inhibition is associated with significant side effects. Thus there is a rationale for identifying and targeting signalling mechanisms downstream of the Notch receptor itself. Brennan lab has previously shown that Notch confers resistance to drug-induced apoptosis in breast cancer cells, through activation of pro-survival Akt signalling. This novel signalling axis is mediated by the cytokine IL-1α. Unlike Notch, little is known about the role of IL-1 signalling in the breast cancer cell phenotype. Here I present data which demonstrates the importance of IL-1 signalling in the breast cancer cell phenotype, including in invasion and apoptosis resistance. It is shown that IL-1 is important in the ability of breast cancer cells to form xenograft tumours in vivo, and that IL-1 signalling may be enriched in the breast cancer stem cell compartment. The role of IL-1 signalling appears to differ between ER- and ER+ breast cancers, implicating the pathway specifically in the triple negative subtype. Additionally, I confirm that IL-1α is activated downstream of canonical Notch signalling, and is key to the apoptosis resistance observed as a consequence of aberrant Notch activation. It is revealed that IL-1 activates pro-survival Akt signalling through direct interaction between IL-1R1 and PI3K. Finally, the IL-1 signalling pathway is investigated in the normal mammary gland in vivo. We show for the first time that loss of IL-1 signalling accelerates mammary gland early involution. Collectively these data support the hypothesis that Notch/IL-1 signalling could be targeted as part of a novel combination breast cancer therapy. IL-1 signalling inhibitors are already used extensively in the clinic for inflammatory disorders, and are well tolerated with a lengthy safety record. This makes them prime for re-appropriation into cancer therapy.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andrew Gilmore (Supervisor) & Keith Brennan (Supervisor)