With more than a quarter century of study, the high temperature superconducting cuprates still represent one of the most active areas of research in condensed matter physics. Its complex phase diagram continues to present challenges to our understanding, stemming from its correlated electronic nature. Being able to tease out the effect of different lattice orderings and their effects on electronic states may be crucial to understanding the physics of the cuprates where such orderings may be crucial to the phase diagram. Thus, because of its ability to directly probe electronic band structure, Angle Resolved Photoemission Spectroscopy (ARPES) is an ideal probe to study the effects of competing orders on electronicstates near EF.

This thesis will be organized in the following way. Chapter 1 provides a broad introduction to the physics central to our work including concepts of band structure and Fermi liquid theory, as well as more exotic phenomena explored throughout the thesis. Chapter 2 introduces the ARPES technique, how it is physically understood via concepts like Green's functions, and traditional methods of data analysis. Chapter 3 explores magnetic ordering and its effect on both core level and valance band states in the iron oxypnictides. From the near-EF electronic states, we find that the magnetic physics of the parent compound may still be present even at superconducting dopings. Chapter 4 explores charge density wave (CDW) ordering by looking at the rare earth ditellurides. This ARPES work establishes LaTe2 as the first quasi-2D CDW system to behave like a true Peierls transition, with both Fermi surface nesting tied to a metal - to - insulating transition. Chapter 5 explores the effect

of lattice strain on electronic states by studying the single layered Bi2201 cuprates with lanthanide substitution. The effect of this substitution competes with superconductivity and appears to enhance bosonic modes acting on the nodal point states which are otherwise unaffected. Chapter 6 takes the specific case of Nd-Bi2201 and finds evidence of a distinct crossover point in the electronic states near EF segregating the nodal point states. Finally, Chapter 7 provides a summary of our work and its conclusions.

Epithelial-mesenchymal transition (EMT) is a conserved cellular plasticity program that is reactivated in carcinoma cells and drives metastasis. EMT is well studied, but its regulatory mechanisms remain unclear. In this dissertation, we explore two ways in which the ubiquitin-proteasome system regulates EMT.

First, we investigate the role of the 26S proteasome in regulating EMT. In Chapters 1-2, we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy.

Second, we explore potential novel regulators of EMT within the ubiquitin-proteasome system pathway. In Chapters 3-4, we uncover novel regulators of EMT by mining previously published microarray data and found a group of deubiquitinases (DUBs) upregulated in cells that have undergone EMT. Here, we show that one DUB in particular, Ubiquitin specific peptidase 11 (USP11), enhances TGF-β-induced EMT and self-renewal in immortalized human mammary epithelial cells. Furthermore, modulating USP11 expression in human breast cancer cell lines altered migratory capacity in vitro and metastasis in vivo. Moreover, we found that high USP11 expression in human breast cancer patient clinical samples correlated with decreased survival. Mechanistically, modulating USP11 expression altered the stability of TGF-β receptor type 2 (TGFBR2) and TGF-β downstream signaling in human breast cancer cell lines. Together, these data suggest that deubiquitination of TGFBR2 by USP11, effectively spares TGFBR2 from proteasomal degradation to promote EMT and metastasis and suggest USP11 as a potential therapeutic target for breast cancer.

ABSTRACT

Using switchable mouse models to assess the

therapeutic potential of MdmX and E2F3

by

Daniel Garcia

Diverse as tumors are, they share some common features that are hallmarks of cancer. Two of these hallmarks are the evasion of tumor surveillance mechanisms and deregulated proliferation. Aiming to address these problems, we have used novel switchable mouse models to test the therapeutic potential of MdmX and E2F3, two genes directly involved in allowing tumor cells to evade tumor suppression and to proliferate, respectively.

MdmX is a critical negative regulator of p53 whose over-expression in many cancers is thought to block p53 tumor suppressor function. Consequently, inhibiting MdmX has emerged as an intriguing approach to restoring p53 function in established cancers. However, MdmX-deficient mice exhibit p53-dependent death early in embryogenesis, which has precluded elucidation of the consequences of systemic MdmX inhibition. To determine directly the effects of systemic MdmX inhibition in normal adult tissues and in tumors, we crossed mdmX-/- mice into the p53ERTAM knock-in background to obtain adult MdmX-null mice in which p53 function can be restored. p53 became active when transiently restored in these mice, but the effects of this activity were non-lethal and reversible. Moreover, absence of MdmX enhanced p53 restoration therapy in a mouse model of lymphoma. Hence, systemic inhibition of MdmX is a feasible therapeutic strategy for restoring p53 function in tumors that retain wild type p53.

The E2F family of transcription factors plays a key role in a number of cellular processes, including cellular proliferation and tumorigenesis. E2Fs are deregulated in the vast majority of cancer and appear to be essential conduits for upstream oncogenic lesions. Recent genetic studies in mice have established E2F3 as the most essential activating E2F for cellular proliferation and embryonic viability. However, the embryonic lethality of E2F3-null mice has prevented the study of the contribution of E2F3 to tumor proliferation and the assessment of E2F3 inhibition as a therapeutic avenue. To directly study E2F3 biology in adult tissues and tumors, we established a novel tet-repressor system that allows control of endogenous e2f3 expression in adult mice.

With the current interest in the rare-earth tellurides as high temperature charge density wave materials, a greater understanding of the physics of these systems is needed, particularly in the case of the ditellurides. We report a detailed study of the band structure of LaTe_2 in the charge density wave state using high-resolution angle resolved photoemission spectroscopy (ARPES). From thiswork we hope to provide insights into the successes and weaknesses of past theoretical study as well as helping to clear up prior ambiguities by providing an experimental basis for future work inthe tellurides.