Defining the roles of endothelial adhesion receptors during mammary gland development, functional differentiation, and cancer

Fowler, Wesley (2020) Defining the roles of endothelial adhesion receptors during mammary gland development, functional differentiation, and cancer. Doctoral thesis, University of East Anglia.

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Angiogenesis is a fundamental process entailing the generation of nascent vasculature from pre- existing blood vessels. Driven by endothelial cells (ECs) in response to pro-angiogenic factors, the angiogenic cascade results in the upregulation of multiple essential proteins in these cells; including integrin-β3, integrin-α5 and neuropilin-1. All three molecules are attractive anti-angiogenic targets. Despite an array of studies supporting their druggability, attempts at targeting them in patients have failed. With breast cancer (BC) being the second most common cancer globally, gaining an understanding of how angiogenesis affects the development of the mammary gland throughout its lifecycle will provide insight into why current anti-angiogenics are ineffective. I hypothesized that the ablation of these three molecules to impede angiogenesis during different stages of the mammary life cycle would offer the opportunity to ascertain how angiogenesis influences mammary epithelial morphogenesis. I developed model systems in which I can deplete the EC expression of integrin-β3, integrin-α5 and neuropilin-1, simultaneously, and then study the effects of this depletion on the mammary gland in vivo, or on mammary ECs in vitro. My findings show that impairing the angiogenesis that is mediated by these three proteins during pubertal development of the gland has minor effects on mammary ductal branching morphogenesis. Similarly, there is little to no effect on mammary alveolar development during gestation and early lactation. However, I uncovered changes in placental development that may help to explain these findings. In contrast to what happens during the physiological life cycle of the mammary gland, I observed a significant reduction in BC growth when all three targets were depleted, suggesting pathological development of the breast is dependent on angiogenesis driven by integrin-β3, integrin-α5 and neuropilin-1. Lastly, the in vitro study of mammary ECs provide insight into potential alternative signalling pathways through which the mammary gland may achieve angiogenesis, specifically, via progesterone.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Nicola Veasy
Date Deposited: 07 Oct 2021 13:22
Last Modified: 07 Oct 2021 13:22

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