Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance

Abstract

The protein quality control network, including autophagy, the proteasome and the unfolded protein response (UPR), is triggered by stress and is overactive in acquired antiestrogen therapy resistance. We show for the first time that the aggresome load correlates with apoptosis and is increased in antiestrogen-sensitive cells compared to endocrine-resistant variants. LC-MS/MS analysis of the aggregated proteins obtained after 4OH-tamoxifen and Fulvestrant treatment identified proteins with essential function in protein quality control in antiestrogen-sensitive cells, but not in resistant variants. These include the UPR modulators RTCB and PDIA6, as well as many proteasome proteins such as PSMC2 and PSMD11. RTCB is a tRNA and XBP1 ligase and its aggregation induced by antiestrogens correlated with impaired XBP1s expression in sensitive cells. Knock down of RTCB was sufficient to restore sensitivity to tamoxifen in endocrine-resistant cells and increased the formation of aggresomes, leading to apoptotic cell death. Analysis of primary human breast cancer samples and their metastases appearing after endocrine treatment showed that RTCB is only localized to aggresomes in the primary tumors, while total aggresomes, including aggregated RTCB, were significantly reduced in the metastases. Therefore, different protein aggregation patterns may indicate loss of function of essential proteins resulting in enhanced protein aggregation that can be used to identify antiestrogen-resistant breast cancer cells and improve the response to antiestrogenic therapy.

The Impact of Fast-Rise-Time Electromagnetic Field and Pressure on the Aggregation of Peroxidase upon Its Adsorption onto Mica

“…Furthermore, protein aggregation was reported to be associated with cancer in humans: Xu et al [12] reported that aggregation processes, which involve mutant p53 protein, are associated with the development of cancer, which could thus be considered as aggregationassociated disease. This was confirmed in the research performed by other authors [13][14][15]. Another well-known fact is that the formation of amyloid aggregates in the brain was considered to lead to Parkinson's [16] and Alzheimer's [16][17][18] diseases.…”

“…Another example is the FXR1 protein, which is involved in the regulation of memory and emotions [16]. However, protein oligomers are also known to be involved in the development of pathological processes in the body, such as cardiovascular [11] and oncological [12][13][14][15] diseases. This should be taken into account in the development of modern medical strategies aimed at correcting protein aggregation induced by the above-described factors.…”

Metabolic Adaptations in an Endocrine-Related Breast Cancer Mouse Model Unveil Potential Markers of Tumor Response to Hormonal Therapy

“…Moreover, HIR tumors exhibit similar levels of GSH, taurine and m -inositol to other tumors, indicating similar extension of active anti-oxidative mechanisms also associated with ET resistance ( 73 ), however they are distinguished by the lowest glutamate levels (and low alanine) within the tumors, which possibly are consumed to produce GSH. UDP-GlcNAc is also upregulated in HIR but to a lesser extent than in HI tumors maintaining a relevant protein glycosylation activity; still, it is worth mentioning that endocrine resistant breast cancer cells increase their endoplasmic reticulum capacity (through the activation of unfolded protein response), which is one of the major cellular organelles where protein glycosylation occurs ( 74 , 75 ). In HIR tumors, the lowest GPC levels (within the tumors) again seems to reflect a distinct status of membrane metabolism where lower GPC may be the result of higher phospholipid (phosphatidylcholine, main membrane constituent) synthesis.…”

SETD7 Expression Is Associated with Breast Cancer Survival Outcomes for Specific Molecular Subtypes: A Systematic Analysis of Publicly Available Datasets

“…This may be specifically relevant for the luminal B subtype, where the most significant biological processes overrepresented in the high-SETD7 (mRNA) group were the ubiquitin-dependent ERAD pathway and the positive regulation of autophagy, which is also linked to the ubiquitin–proteosome system (UPS, also overrepresented). The association with high SETD7 was not strong, but given that these two pathways underly endocrine resistance [ 60 , 61 ], the additive contribution of all these genes to these processes should not be discarded. Autophagy is associated with the suppression of tumour initiation [ 62 ] and the survival of dormant BC stem cells and metastatic tumour recurrence [ 62 , 63 ].…”