Year: 2014
Type: dissertation
Abstract: Deregulation of cancer metabolism is one of the biological features that drive\n\ncarcinogenesis. In this study, the roles of nuclear receptors (NRs) in nutrient and drug\n\nmetabolism in cancer cells were investigated. Studies have shown an association\n\nbetween diabetes and breast cancer and here we sought to investigate the crosstalk\n\nbetween estrogen and insulin signaling. Estradiol induced growth of insulin primed\n\nMCF-7 cells but had no significant effect on unprimed MCF-7 cells. Interestingly,\n\nalthough estradiol-induced growth was mediated through estrogen receptor (ER),\n\nthe comparable expression of ER between insulin primed and unprimed cells\n\nsuggests that ER alone does not account for estradiol-induced growth and that an\n\nadditional factor may be required. The lack of estradiol growth induction in the\n\npresence of PI3K and Erk inhibitors coupled with the estradiol-induced\n\nphosphorylation of Akt and Erk proteins indicates a cross talk between ER signaling\n\nand PI3K/Akt and Erk signaling pathways. Estradiol treatment induced the expression\n\nof cyclin A and cyclin B in an ER-dependent manner, suggesting estradiol promotes \nxii\n\ncell cycle progression. Finally, metformin but not thiazolidinediones, which are well\n\nknown anti-diabetic drugs, inhibited estradiol-induced growth, suggesting that\n\nmetformin treatment of breast cancer patients with diabetes would improve the\n\noutcome of the breast cancer.\n\nThe roles of NRs in drug metabolism by determining their potential as\n\ncombinational partners with other anti-cancer drugs were also investigated. To that\n\nend, all 48 NRs and 48 biological anti-cancer targets in six pairs of lung cell lines,\n\nwhere each pair was obtained from the same patient, were profiled. Analysis of the\n\nexpression profile revealed that some NRs and anti-cancer targets had distinct\n\nexpression patterns in normal versus tumor cells and primary tumor versus metastatic\n\ncell lines. Remarkably, the evaluation of nuclear receptor ligand TO901317 for liver\n\nX receptor (LXR) demonstrated its combined potential with cMET inhibitor\n\n(PHA665752) or epidermal growth factor (EGFR) inhibitor (gefitinib) in H2073 and\n\nH1993. Mechanistically, combined treatment suppressed cell cycle progression by\n\ninhibiting cyclin D1 and cyclin B. Taken together, this study gives possible links\n\nbetween diabetes and breast cancer as well as the potential use of NR ligands in\n\ncombined therapeutics with other anti-cancer drugs
Author: 페니나 와이라구
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2944762338