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The Notch and EDAR signalling pathways in mammary gland development and tumourigenesis
[Thesis]. Manchester, UK: The University of Manchester; 2011.
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Abstract
Worldwide, more than 1,000,000 women develop breast cancer each year, and more than 400,000 die because of it. Basal-like breast cancers, which account for 8% to 20% of all breast cancer cases, represent the most aggressive of breast cancers with the majority resistant to existing targeted therapies. Accumulating lines of evidence implicate the Notch pathway in the aetiology of these basal-like breast cancers; while current work in our lab supports the notion that signalling through the Ectodermal Dysplasin Receptor (EDAR) pathway is also important. Notch signalling functions in normal development to control cell fate decisions and is mediated primarily, although not exclusively, through the CBF1 / RBP-Jĸ transcription factor. Aberrant Notch signalling leads to mammary tumourigenesis in mice; however at the outset of this work it was unclear whether signalling through RBP-Jĸ and / or through alternative pathways is required. This thesis presents novel data showing that elevated Notch signalling through the RBP-Jĸ-dependent pathway alone in murine mammary glands causes a number of developmental defects, including reduced ductal outgrowth, increased ductal side branching at puberty and, most significantly, is sufficient to induce mammary tumourigenesis. The data presented also provide supporting evidence that Notch signalling through RBP-Jĸ likely contributes to tumourigenesis, at least in part, via the suppression of apoptosis. At the outset of this thesis far less was known regarding the role(s) of the EDAR pathway within the mammary gland. Despite its recognised function in the development of ectodermal appendages it has been predominantly studied in the context of hair and tooth development. We show here that elevated Edar signalling affects the morphology of numerous ectodermally-derived glands, including the mammary gland, where in general, it results in glands that are enlarged or more elaborately branched. Most significantly, we show that elevated Edar signalling causes mammary tumourigenesis in mice, and provide data to support the hypothesis that elevated EDAR signalling might also be important in a subset of basal-like breast cancers in humans. The murine mammary gland phenotypes seen in response to elevated Edar signalling, including the squamous metaplasia within Edar-induced tumours, are very similar to those observed when Wnt signalling is increased. We provide data to support a positive correlation between activation of the EDAR and Wnt pathways in murine mammary tumourigenesis and provide data to support a comparable interaction in the aetiology of basal-like breast cancer showing squamous differentiation in humans. In summary, this thesis identifies the EDAR pathway as a novel potential therapeutic target in the treatment of a subset of basal-like breast cancers, and provides evidence that signalling through the RBP-Jĸ-dependent Notch pathway is sufficient to induce mammary tumourigenesis, most likely through the suppression of apoptosis.