Impact of Variants in Atp-Binding Cassette Transporters on Breast Cancer Treatment

Abstract

There has been substantial interest in the impact of ATP-binding cassette (ABC) transporter variability on breast cancer drug resistance. Here, we provide a systematic review of ABC variants in breast cancer therapy. Notably, most studies used small heterogeneous cohorts and their identified associations lack statistical stringency, replication and mechanistic support. We conclude that commonly studied ABC polymorphisms are not suitable to accurately predict therapy response or toxicity in breast cancer patients and cannot guide treatment decisions. However, recent research shows that ABC transporters harbor a plethora of rare variants with individually small effect sizes, and we argue that a shift in strategy from target variant interrogation to comprehensive profiling might hold promise to drastically improve the predictive power of outcome models.

Robust Identification of Differential Gene Expression Patterns from Multiple Transcriptomics Datasets for Early Diagnosis, Prognosis, and Therapies for Breast Cancer

“…Understanding the intricate links between the ECM and cellular functions has aided in the discovery of disease markers and therapeutic targets [156]. The top-ranked five MFs (Protein Tyrosine Kinase Activator Activity, Protein Kinase Activator Activity, ATP Binding, Transforming Growth Factor Beta Binding, and Ubiquitin Conjugating Enzyme Activity) play a vital role in BC development and proliferation [127,[157][158][159][160]. We identified the top five enriched common KEGG pathways (adipocytokine signaling pathway, protein digestion, and absorption, insulin resistance, AMPK signaling pathway, fatty acid biosynthesis) that were also reported by some individual research.…”

Computational Tools to Assess the Functional Consequences of Rare and Noncoding Pharmacogenetic Variability

“…The most extensively studied example is a haplotype consisting of two synonymous variants (rs1128503 and rs1045642 corresponding to p.G412G and p.I1145I) in ABCB1 (encoding Pgp/MDR1) that disrupts cotranslational folding of the transporter 47 . The variants are further in high linkage disequilibrium with the putatively neutral triallelic missense variant rs2032582 (p.S893A/T), and the haplotype has been associated with toxicity and response to taxanes in breast cancer patients 48 . Furthermore, synonymous haplotypes in COMT affect translation, 49 thereby potentially altering the metabolism of COMT substrates, such as levodopa and methyldopa.…”

“…47 The variants are further in high linkage disequilibrium with the putatively neutral triallelic missense variant rs2032582 (p.S893A/T), and the haplotype has been associated with toxicity and response to taxanes in breast cancer patients. 48 Furthermore, synonymous haplotypes in COMT affect translation, 49 thereby potentially altering the metabolism of COMT substrates, such as levodopa and methyldopa. Due to the limited number of synonymous variants with confirmed effects on gene activity, benchmarking of the available methods for pharmacogenetic applications remains difficult.…”

Application progress of immobilized biomembrane in the discovery of active compounds of natural products

“…Modern research shows that the effects of drugs are determined by their ability to interact with transmembrane proteins and/or cytoplasm (Matera & Tata, 2014), and more than 60% of drug targets are confirmed to be membrane proteins (Yin & Flynn, 2016). For example, the ATP‐binding cassette transporter is one of the targets of anti‐cancer substances, including alkaloids, anthracyclines, and other cytotoxic drug substrates (Xiao et al, 2020). In addition, some diseases, such as systemic lupus erythematosus, having unknown targets but the acting cell is clear (B lymphocyte), are more suitable for screening using biomembranes (Bag‐Ozbek & Hui‐Yuen, 2021).…”