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

Abstract

Simple SummaryResistance to tamoxifen treatment is an obstacle for ER+ve breast cancer therapy. The overexpression of c-MYC is a known driver of cancer progression and is associated with tamoxifen resistance. Through mediating the up-regulation of ribosome biogenesis and alteration of the transcriptome, c-MYC modulates the translation profile to facilitate the development of tamoxifen resistance. c-MYC is, however, undruggable. Thus, targeting downstream mechanisms mediated by c-MYC might be a more feasible approach. Studies have demonstrated that inhibition of ribosome biogenesis can achieve tumour suppression. Targeting ribosome biogenesis may thus be a feasible strategy to reverse tamoxifen resistance. This article reviews the current evidence to support the feasibility of suppressing ribosome biogenesis to reverse tamoxifen resistance in ER+ve breast cancer.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.