Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Peeyush K Lala

Abstract

Cyclooxygenase-2 (COX-2) is overexpressed in 40-50% of breast cancers, and promotes tumour progression through increased proliferation, migration, invasion, Epithelial-to-Mesenchymal Transition (EMT), and induction of therapy-resistant Stem-Like-Cells (SLCs). COX-2 stimulates expression of two oncogenic and SLC-promoting microRNAs (miR-526b, miR-655), which simultaneously target one gene, Cytoplasmic Polyadenylation Element Binding Protein-2 (CPEB-2). Hypothesis: CPEB-2 is a tumour- and SLC-suppressing gene in breast cancer. Results: CPEB-2 knockout in a non-tumourigenic mammary epithelial cell line MCF10A demonstrated increases in proliferation, migration, invasion, EMT markers, SLC content, and VEGF-D expression. CPEB-2, an mRNA-binding translation-regulating protein, was found to regulate the translation of tumour suppressor p53. When intravenously injected into NOD/SCID/IL2Ry-null mice, CPEB2KO cells formed micrometastases in the lung, and after orthotopic injection into the mammary region, they formed tumours in 3/5 mice, including spontaneous lung metastases. Isoform A/E of CPEB-2 was decreased in HER2+ breast cancer samples. Conclusion: CPEB-2 is a tumour-suppressing gene in breast cancer.

Available for download on Sunday, June 02, 2019


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