Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure.
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ABSTRACT:
SUBMITTER: Tonetti DA
PROVIDER: S-EPMC2741052 | biostudies-other | 2003 May
REPOSITORIES: biostudies-other
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Project description:Choline kinase-? (Chk-?) and autophagy have gained much attention, as they relate to the drug-resistance of breast cancer. Here, we explored the potential connection between Chk-? and autophagy in the mechanisms driving to tamoxifen (TAM) resistance, in estrogen receptor positive (ER+) breast cancer cells (BCCs). Human BCC lines (MCF-7 and TAM-resistant MCF-7 (MCF-7/TAM) cells) were used. Chk-? expression and activity was suppressed by the transduction of shRNA (shChk-?) with lentivirus and treatment with CK37, a Chk-? inhibitor. MCF-7/TAM cells had higher Chk-? expression and phosphocholine levels than MCF-7 cells. A specific downregulation of Chk-? by the transduction of shChk-? exhibited a significant decrease in phosphocholine levels in MCF-7 and MCF-7/TAM cells. The autophagy-related protein, cleaved microtubule-associated protein light chain 3 (LC3) and autophagosome-like structures were significantly increased in shChk-?-transduced or CK37-treated MCF-7 and MCF-7/TAM cells. The downregulation of Chk-? attenuated the phosphorylation of AKT, ERK1/2, and mTOR in both MCF-7 and MCF-7/TAM cells. In MCF-7 cells, the downregulation of Chk-? resulted in an induction of autophagy, a decreased proliferation ability and an activation of caspase-3. In MCF-7/TAM cells, despite a significant decrease in proliferation ability and an increase in the percentage of cells in the G0/G1 phase of the cell cycle, the downregulation of Chk-? did not induced caspase-dependent cell death and further enhanced autophagy and G0/G1 phase arrest. An autophagy inhibitor, methyladenine (3-MA) induced death and attenuated the level of elevated LC3 in MCF-7/TAM cells. Elucidating the interplay between choline metabolism and autophagy will provide unique opportunities to identify new therapeutic targets and develop novel treatment strategies that preferentially target TAM-resistance.
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Project description:Resistance to tamoxifen therapy represents a major barrier to the successful treatment of breast cancer, where a loss of or reduced ER-α level is considered a primary mechanism. Understanding how ER-α expression is regulated would provide insights into new intervention points to overcome tamoxifen resistance. In this study, we report that the expression of δEF1 is up-regulated by 17β-estradiol (E2) in MCF-7 cells in an ER-α-dependent manner, through either PI3K or NF-κB pathway. Ectopic expression of δEF1 in turn repressed ER-α transcription by binding to the E(2)-box on the ER-α promoter. At the tissue level of breast cancer, there is a strong and inverse correlation between the expression levels of δEF1 and ER-α. In MCF-7 cells, an elevated expression of δEF1 made the cells less sensitive to tamoxifen treatment, whereas overexpression of ER-α compromised the effects of δEF1 and restored the sensitivity. Also, depletion of δEF1 by RNA interference in MDA-MB-231 cells restored the expression of ER-α and tamoxifen sensitivity. In conclusion, we have identified an important role of δEF1 in the development of tamoxifen resistance in breast cancer. Inhibiting δEF1 to restore ER-α expression might represent a potential therapeutic strategy for overcoming endocrine resistance in breast cancer.
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