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The causes and consequences of regulation of [Delta]NP63[alpha] in mammary and breast cancer stem cells / by Andrew Joseph DeCastro.

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Author	DeCastro, Andrew Joseph.
Title	The causes and consequences of regulation of [Delta]NP63[alpha] in mammary and breast cancer stem cells / by Andrew Joseph DeCastro.
Date	2014
Abstract	Despite the array of targeted therapeutics that currently exist to combat breast cancer, disease progression leading to metastasis, and tumor recurrence still remains a significant clinical challenge. Efforts to identify novel pathways and mechanisms that mediate metastasis or recurrence has focused on a small subset of cells in the mammary gland and breast tumors known as mammary stem cells and breast cancer stem cells respectively. Akin to normal mammary stem cells, breast cancer stem cells also possess the ability to retain self-renewing capabilities, a prolonged life span and developmental potency, identifying them as a critical component of therapeutic resistance and metastatic development. The pathways and mechanisms that are utilized to mediate such phenotypes in these cell populations are poorly understood, and elucidation of such mechanisms may lead to the development of more effective therapeutic strategies. The predominant isoform of the TP63 gene, [Delta]NP63[alpha] is implicated in the self-renewal and preservation of epithelial stem cells, including mammary stem cells. However, the mechanisms by which this regulation is achieved, and [Delta]NP63[alpha]'s role in cancer stem cells and metastasis remains poorly understood. Data from experimental studies presented in this dissertation define a regulatory pathway in which the microRNA, MIR203 mediates the forfeiture of self-renewing capacity in mammary stem cells during differentiation through the repression of [Delta]NP63[alpha] expression. Moreover, mature miR-203 expression was inversely correlated with an aggressive, pro-invasive phenotype in a panel of breast cancer cell lines, suggesting a role for [Delta]NP63[alpha] in breast cancer progression. As a result, we sought to identify targets of [Delta]NP63[alpha] that may mediated such tumorigenic activities. Here, we present data identifying the pro-metastatic chemokine receptor 4 gene (CXCR4) as a direct transcriptional target of [Delta]NP63[alpha], which subsequently mediates [Delta]NP63[alpha]'s cancer stem cell activities and chemotactic phenotype in breast cancer cells. This work suggests that [Delta]NP63[alpha] may identify and regulate tumor-initiating cancer stem cells of high metastatic potential, which may be clinically relevant to target therapeutically to reduce breast cancer progression and metastasis.
Description	xix, 189 leaves : ill. (some col.)
Format	application/pdf
College	Dartmouth College. Experimental and Molecular Medicine Program. NhDDartmouth Medical School.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.1244

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