Elucidating the molecular pathways associated with Cholesteryl Ester Transfer Protein (CETP) knockdown in estrogen receptor positive breast cancer
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Date
2020
Authors
Pillay, Ruvesh Pascal
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Abstract
The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol aids cancer cell proliferation and survival. Previous studies from our laboratory have implicated the Cholesteryl Ester Transfer Protein (CETP), in the involvement of breast cancer aggressiveness via cholesterol accumulation. Interestingly, the abrogation of CETP resulted in significant cell death in MCF-7breast cancer cells(estrogen receptor positive), which also sensitised cells to currently available cytotoxic cancer agents, such as Tamoxifen even at low concentrations. Thus, this study displayed CETP’s role as potential cancer survival gene and drug resistance marker. The current study investigated the effect of CETP knockdown (in MCF-7 cells) on cholesterol levels and changes in expression of genes that are involved in lipoprotein signalling and cancer drug resistance. The study therefore focused on elucidating the molecular mechanisms underlying CETP’s involvement in cancer, particularly, ER+ breast cancer. Intriguingly, CETP knockdown resulted in reduction in cholesterol especially when treated with a cholesterol depletory agent (Acetyl-plumbagin), decreasing the viability of these cancer cells. Furthermore, there was an overall downregulation of genes involved in cholesterol biosynthesis, including genes of the mevalonate pathway (HMGCS1, HMGCR, MVD), as well as genes that code transcription factors for cholesterol synthesis (SREBPF1), post-CETP knockdown. Additionally, LDLR, the principal receptor involved in exogenous cholesterol uptake was also significantly downregulated. Cancer drug resistance gene expression analysis revealed a downregulation of genes coding growth factor receptors (ESR1, IGF1RHER2), drug efflux pumps (ABCB1) and anti-apoptotic BCL2. The principal findings of this study display the possible role of downregulating CETP to limit drug resistance and cholesterol accumulation in cancer cells, thereby reducing breast cancer aggressiveness
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A dissertation submitted in fulfilment of the requirements for the degree Master of Science in Molecular and Cell Biology in the Faculty of Science, University of the Witwatersrand, Johannesburg, 2020