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

Abstract

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.

Multi-Omics Analysis Revealed a Significant Alteration of Critical Metabolic Pathways Due to Sorafenib-Resistance in Hep3B Cell Lines

“…Ribosome aids in upsurging protein synthesis to support cancer growth [ 104 ]. In a recent published article, it was stated that ribosomal biogenesis up-regulation and transcriptome alteration aid in tamoxifen resistance development via translation profile modulation of c-MYC, which is linked to tamoxifen resistance [ 105 ]. Aminoacyl-tRNA biosynthesis plays a key role in transferring amino acids to tRNA in protein translation and protein biogenesis [ 106 ].…”

Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway

“…Being one of the oldest selective estrogen receptor modulators, tamoxifen has been serving as the first line of adjuvant endocrine therapy for primary and metastatic ER + breast cancer patients 56 . However, resistance to tamoxifen therapy is possible and other therapeutic agents are required 57 .…”

POR overexpression induces tamoxifen‐resistance in breast cancer through the STAT1/c‐Myc pathway

“…TAM, as a selective ER modulator, is commonly used for ER-positive breast cancer patients 4,5 . We then investigated whether POR expression was associated with TAM resistance in breast cancer patients.…”

“…Tamoxifen (TAM), a selective ER modulator, is one of the most successful and widely used chemopreventive agents ever and is an effective therapeutic agent for inhibiting the growth of ER‐positive breast cancers 3 . However, approximately 30%–40% of ER‐positive patients do not respond to TAM initially, or gradually develop resistance 4 . Therefore, TAM resistance remains a significant therapeutic challenge for ER‐positive breast cancer 5,6 …”

“…3 However, approximately 30%-40% of ER-positive patients do not respond to TAM initially, or gradually develop resistance. 4 Therefore, TAM resistance remains a significant therapeutic challenge for ER-positive breast cancer. 5,6 NADPH-dependent cytochrome P450 reductase (POR), an important flavoprotein localized at the endoplasmic reticulum membrane, 7 participates in many important physiological and biochemical reactions such as drug metabolism and steroid metabolism.…”