Author: Tung Bui

Publisher:

Published: 2019

Total Pages:

ISBN-13:

"Breast cancer progression involves well-defined pathological and clinical stages starting with epithelial hyperproliferation, subsequent evolution into in situ and invasive carcinomas, and finally distal metastases. Although tumor initiation and progression are predominantly driven by acquired genetic alterations, recent data also implicate a supportive role for microenvironmental changes as well. Breast cancer is not a single disease entity but a highly heterogeneous group comprising of several distinct subtypes. Given the complexity of breast cancer, genetically engineered mouse models (GEMMs) have been instrumental in our understanding of malignant transformation. Mammary ducts are comprised of highly organized epithelial cells ensuring the maintenance of tissue homeostasis and tissue architectural integrity via two key classes of cell adhesion: cell-to-cell, and cell-to-extracellular matrix (ECM). Progressive disruption of both types of cell adhesion cooperates with oncogenic activation or tumor suppressor loss to drive malignant transformation. Utilizing GEMMs that faithfully recapitulate human disease, we have highlighted complex and highly context-dependent roles of two classes of cell adhesion proteins: [beta]-catenin (for cell-cell adhesion) and integrins (for cell-ECM adhesion). In the second chapter of the thesis, I show that deletion of [beta]-catenin in a GEMM of basal ErbB2-positive breast cancer reveals complex roles of this protein, due to its functional duality as a structural and a signaling molecule. We show that [beta]-catenin is required for proper adherens junction formation and that consequently, [beta]-catenin haploinsufficiency promotes aggressive tumor formation and metastasis. Defective adherens junctions permit the remaining pool of [beta]-catenin to engage predominantly in its transcriptional activity and promote dedifferentiation and epithelial-to-mesenchymal transition. This haploinsufficient phenotype is unique to a basal ErbB2-positive model with a pre-existing aberrant activation of [beta]-catenin signaling, but not in a model of luminal ErbB2-positive cancer lacking such activity. Taken together, our data argue that the balance of junctional and nuclear [beta]-catenin activity has a profound impact on tumorigenesis in a subtype-dependent manner. In the third chapter of the thesis, I provide genetic evidence to support a functional redundancy between two integrin subunits, [beta]1 and [beta]3, in ErbB2-driven breast cancer. In the absence of [beta]1 integrin, [beta]3 integrin is upregulated to promote tumor initiation, tumor growth and lung metastasis. Mammary-specific disruption both [beta]1 and [beta]3 subunits results in a dramatic delay in ErbB2 tumor progression that is further correlated with a reduction in PI3K/Akt/mTORC1 signaling activity. Mechanistically, [beta]1/[beta]3 integrin receptors engage stiff ECM to recruit insulin receptor INR to the plasma membrane and therefore prevent its lysosomal degradation. Overall, this study emphasizes an important functional crosstalk between integrins and RTK in transducing mechanical cues from tumor microenvironment (TME) to promote breast cancer progression. Finally, in the fourth chapter, I demonstrate a critical role for [beta]1 integrin receptors in a GEMM of luminal B breast cancer. I identify a critical role for [beta]1 integrin receptors in overcoming initial tumor suppressive barriers and thereby permitting efficient transition between pathological stages to give rise to metastatic breast malignancy. However, a small fraction of tumors circumvents the loss of [beta]1 integrin by engaging distinct evolution trajectory including numerous genetic aberrations and extensive remodelling of the TME. In particular, TME exhibits features of chronic inflammation, including increases in ECM deposition, angiogenesis, cancer-associated fibroblast and M2 macrophage infiltration, and pro-inflammatory cytokine production. The mechanisms by which deletion of [beta]1 integrin elicits such inadvertent adaptions remain to be elucidated. " --