Targeting Ribosome Biogenesis to Combat Tamoxifen Resistance in ER+ve Breast Cancer

• Published in: Cancers Vol. 14; no. 5; p. 1251
• Main Authors: Tsoi, Ho, You, Chan-Ping, Leung, Man-Hong, Man, Ellen P. S., Khoo, Ui-Soon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.02.2022; MDPI
• Subjects: Apoptosis; Biosynthesis; Breast cancer; c-Myc protein; Cancer therapies; Cell cycle; Cell division; Cell growth; Cell proliferation; Cyclin-dependent kinases; Endocrine therapy; Estrogen receptors; Estrogens; Gene expression; Genomes; Initiation factor eIF-4E; Kinases; Ligands; Localization; Metabolism; Metastases; Metastasis; MicroRNAs; Myc protein; Proteins; Review; Ribosomes; Tamoxifen; Transcription factors; Transcriptomes; Tumors; breast cancer; eIF4E; tamoxifen resistance; c-MYC; ribosome biogenesis
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14051251

Breast cancer is a heterogeneous disease. Around 70% of breast cancers are estrogen receptor-positive (ER+ve), with tamoxifen being most commonly used as an adjuvant treatment to prevent recurrence and metastasis. However, half of the patients will eventually develop tamoxifen resistance. The overexpression of c-MYC can drive the development of ER+ve breast cancer and confer tamoxifen resistance through multiple pathways. One key mechanism is to enhance ribosome biogenesis, synthesising mature ribosomes. The over-production of ribosomes sustains the demand for proteins necessary to maintain a high cell proliferation rate and combat apoptosis induced by therapeutic agents. c-MYC overexpression can induce the expression of eIF4E that favours the translation of structured mRNA to produce oncogenic factors that promote cell proliferation and confer tamoxifen resistance. Either non-phosphorylated or phosphorylated eIF4E can mediate such an effect. Since ribosomes play an essential role in c-MYC-mediated cancer development, suppressing ribosome biogenesis may help reduce aggressiveness and reverse tamoxifen resistance in breast cancer. CX-5461, CX-3543 and haemanthamine have been shown to repress ribosome biogenesis. Using these chemicals might help reverse tamoxifen resistance in ER+ve breast cancer, provided that c-MYC-mediated ribosome biogenesis is the crucial factor for tamoxifen resistance. To employ these ribosome biogenesis inhibitors to combat tamoxifen resistance in the future, identification of predictive markers will be necessary.