Text

theses

The role of the glutamatergic system in cancer cell homeostasis has expanded exponentially over the last decade. Once thought to participate only in synaptic transmission and neuronal excitability, the presence of functional glutamate receptors has since been demonstrated in peripheral tissues. Most notable is the implication of glutamatergic signaling in the pathophysiology of various human malignancies presenting intriguing possibilities to make glutamate receptors putative novel targets for human cancers. Our group previously described the oncogenic properties of metabotropic glutamate receptor 1 (mGluR1/Grm1), a GPCR, in melanoma development in vivo. TG-3, a transgenic mouse line, developed spontaneous melanoma with 100% penetrance in the absence of any known stimuli. Stable Grm1-mouse melanocytic clones display transformed phenotypes in vitro and were aggressively tumorigenic in vivo. This thesis has two key aims. The first is to elucidate key downstream effectors of mGluR1 in melanocyte transformation. MAPK and PI3K/AKT signaling were previously identified as downstream targets of mGluR1. Here, we demonstrate a novel pathway for mGluR1-mediated tumorigenesis involving the transactivation of IGF-1R. Disrupted IGF-1R signaling in stable Grm1-melanocytic cells led to the abolishment of mGluR1-induced AKT activation and the suppression of tumor growth. We propose that IGF-1R activation represents a previously overlooked key pathway involved in the mechanisms by which mGluR1 exerts its transformative properties. In my second aim, as most human cancers are of epithelial origin, we utilized immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the transformative properties of Grm1. Phenotypic alterations in acinar architecture were assessed using 3D morphogenesis assays. We found that mGluR1-expressing iMMECs exhibited delayed lumen formation in association with decreased central acinar cell death, disrupted cell polarity and a dramatic increase in the activation of the MAPK pathway. Orthotopic implantation of mGluR1-expressing iMMEC clones into mammary fat pads of athymic mice resulted in tumor formation. Persistent mGluR1 expression was required for the maintenance of the tumorigenic phenotypes as demonstrated by an inducible Grm1-silencing RNA. Moreover, relevance to human breast cancer may be suggested by the observed expression of mGluR1 in human breast tumor biopsies and cell lines, and the consequences of mGluR1 modulation on tumorigenicity therein. Our findings demonstrate that mGluR1 may be oncogenic in mammary epithelial cells and may play a role in the pathophysiology of breast cancer.

ETD_5025

Ph.D.

Includes bibliographical references

Includes vita

by Jessica Li Fong Teh

doi:10.7282/T3FJ2DT4

ETD doctoral

The author owns the copyright to this work.