Topic Editors

Departamento de Ciências Médicas, IBiMed, Universidade de Aveiro, Aveiro, Portugal
Department of Chemistry, Technological Laboratories, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-093 Aveiro, Portugal
Department of Chemistry, Technological Laboratories, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-093 Aveiro, Portugal

Adaptation Mechanisms in Therapy-Resistant Breast Cancer

Abstract submission deadline
closed (28 February 2023)
Manuscript submission deadline
closed (31 March 2023)
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Topic Information

Dear Colleagues,

The aim of this Topic is to report the recent findings that have increased our understanding of adaptive responses to stress, focusing on resistance to therapy in breast cancer. The usage of omics sciences to characterize cell lines and tumors has uncovered changes in genes, proteins, and other metabolites that result in metabolism adaptation to survive therapy-induced stress. Metabolite changes reflect oncogenic transformation and the remodeling of metabolic pathways, which, in addition to genes and proteins, constitute powerful biomarkers and therapeutic targets. Efforts are needed to go beyond cell line studies and plasma characterization to increase our knowledge of how therapy affects metabolic interplay in the tumor microenvironment. For this Topic, we invite authors to contribute original research, review articles, and meta analyses focusing on metabolic adaptation in hormone receptor-positive breast cancer that promotes or results from therapy resistance. We encourage the submission of articles that explore the biomarker potential of metabolic adaptations, metabolic competition/cooperation between more than one cell type, and the immune tumor microenvironment. Research on the use of novel metabolic modulators to enhance therapy, either natural or synthetic compounds, is also encouraged.

Prof. Dr. Luisa Alejandra Helguero
Dr. Iola F. Duarte
Prof. Dr. Ana M. Gil
Topic Editors

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomolecules
biomolecules
5.5 8.3 2011 16.9 Days CHF 2700
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900
Cells
cells
6.0 9.0 2012 16.6 Days CHF 2700
Current Oncology
curroncol
2.6 2.6 1994 18 Days CHF 2200
Onco
onco
- - 2021 18.3 Days CHF 1000

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Published Papers (8 papers)

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18 pages, 3689 KiB  
Article
Exosome-Transmitted tRF-16-K8J7K1B Promotes Tamoxifen Resistance by Reducing Drug-Induced Cell Apoptosis in Breast Cancer
by Chunxiao Sun, Xiang Huang, Jun Li, Ziyi Fu, Yijia Hua, Tianyu Zeng, Yaozhou He, Ningjun Duan, Fan Yang, Yan Liang, Hao Wu, Wei Li, Yuchen Zhang and Yongmei Yin
Cancers 2023, 15(3), 899; https://doi.org/10.3390/cancers15030899 - 31 Jan 2023
Cited by 4 | Viewed by 1728
Abstract
Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In [...] Read more.
Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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24 pages, 2753 KiB  
Article
eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model
by Alina González-Ortiz, Angel Pulido-Capiz, César Y. Castañeda-Sánchez, Esmeralda Ibarra-López, Octavio Galindo-Hernández, Maritza Anahí Calderón-Fernández, Leslie Y. López-Cossio, Raul Díaz-Molina, Brenda Chimal-Vega, Nicolás Serafín-Higuera, Iván Córdova-Guerrero and Victor García-González
Cells 2022, 11(24), 4069; https://doi.org/10.3390/cells11244069 - 15 Dec 2022
Cited by 2 | Viewed by 2637
Abstract
Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation [...] Read more.
Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5′ untranslated region (5′-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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22 pages, 7093 KiB  
Article
The Clinicopathological Significance of BiP/GRP-78 in Breast Cancer: A Meta-Analysis of Public Datasets and Immunohistochemical Detection
by Inês Direito, Daniela Gomes, Fátima Liliana Monteiro, Isa Carneiro, João Lobo, Rui Henrique, Carmen Jerónimo and Luisa Alejandra Helguero
Curr. Oncol. 2022, 29(12), 9066-9087; https://doi.org/10.3390/curroncol29120710 - 23 Nov 2022
Viewed by 2417
Abstract
The endoplasmic reticulum chaperone BiP (also known as GRP-78 or HSPA5) maintains protein folding to allow cell proliferation and survival and has been implicated in carcinogenesis, tumor progression, and therapy resistance. BiP’s association with clinical factors and prognostic potential in breast cancer remains [...] Read more.
The endoplasmic reticulum chaperone BiP (also known as GRP-78 or HSPA5) maintains protein folding to allow cell proliferation and survival and has been implicated in carcinogenesis, tumor progression, and therapy resistance. BiP’s association with clinical factors and prognostic potential in breast cancer remains unclear. In this work, three types of analysis were conducted to improve the knowledge of BiP’s clinicopathological potential: (1) analysis of publicly available RNA-seq and proteomics datasets stratified as high and low quartiles; (2) a systematic review and meta-analysis of immunohistochemical detection of BIP; (3) confirmation of findings by BiP immunohistochemical detection in two luminal-like breast cancer small cohorts of paired samples (pre- vs. post-endocrine therapy, and primary pre- vs. metastasis post-endocrine therapy). The TCGA PanCancer dataset and CPTAC showed groups with high BiP mRNA and protein associated with HER2, basal-like subtypes, and higher immune scores. The meta-analysis of BiP immunohistochemistry disclosed an association between higher BiP positivity and reduced relapse-free survival. BiP immunohistochemistry confirmed increased BiP expression in metastasis, an association of BiP positivity with HER2 expression, and nuclear BiP localization with higher a tumor stage and poor outcome. Therefore, three independent approaches showed that BiP protein is associated with worse outcomes and holds prognostic potential for breast cancer. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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21 pages, 45049 KiB  
Article
Combination of Immune-Related Network and Molecular Typing Analysis Defines a Three-Gene Signature for Predicting Prognosis of Triple-Negative Breast Cancer
by Jinguo Zhang, Shuaikang Pan, Chaoqiang Han, Hongwei Jin, Qingqing Sun, Jun Du and Xinghua Han
Biomolecules 2022, 12(11), 1556; https://doi.org/10.3390/biom12111556 - 25 Oct 2022
Cited by 4 | Viewed by 1879
Abstract
Recent breakthroughs in immune checkpoint inhibitors (ICIs) have shown promise in triple-negative breast cancer (TNBC). Due to the intrinsic heterogeneity among TNBC, clinical response to ICIs varies greatly among individuals. Thus, discovering rational biomarkers to select susceptible patients for ICIs treatment is warranted. [...] Read more.
Recent breakthroughs in immune checkpoint inhibitors (ICIs) have shown promise in triple-negative breast cancer (TNBC). Due to the intrinsic heterogeneity among TNBC, clinical response to ICIs varies greatly among individuals. Thus, discovering rational biomarkers to select susceptible patients for ICIs treatment is warranted. A total of 422 TNBC patients derived from The Cancer Genome Atlas (TCGA) database and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset were included in this study. High immunogenic gene modules were identified using weighted gene co-expression network analysis (WGCNA). Immune-related genes (IRGs) expression patterns were generated by consensus clustering. We developed a three-gene signature named immune-related gene panel (IRGP) by Cox regression method. Afterward, the associations of IRGP with survival outcomes, infiltration of immune cells, drug sensitivity, and the response to ICIs therapy were further explored. We found five high immunogenic gene modules. Two distinct IRGclusters and IRG-related genomic clusters were identified. The IRGP was constructed based on TAPBPL, FBP1, and GPRC5C genes. TNBC patients were then subdivided into high- and low-IRGriskscore subgroups. TNBC patients with low IRGriskscore had a better survival outcome, higher infiltration of immune cells, lower TP53 mutation rate, and more benefit from ICIs treatment than high IRGriskscore patients. These findings offer novel insights into molecular subtype of TNBC and provided potential indicators for guiding ICIs treatment. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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21 pages, 22786 KiB  
Article
USP7 Induces Chemoresistance in Triple-Negative Breast Cancer via Deubiquitination and Stabilization of ABCB1
by Yueh-Te Lin, Joseph Lin, Yi-En Liu, Yun-Cen Chen, Shiang-Ting Liu, Kai-Wen Hsu, Dar-Ren Chen and Han-Tsang Wu
Cells 2022, 11(20), 3294; https://doi.org/10.3390/cells11203294 - 19 Oct 2022
Cited by 10 | Viewed by 2508
Abstract
Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer. TNBC does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. Cytotoxic chemotherapy and surgery are the current therapeutic strategies for TNBC patients, but the chemoresistance of [...] Read more.
Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer. TNBC does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. Cytotoxic chemotherapy and surgery are the current therapeutic strategies for TNBC patients, but the chemoresistance of TNBC limits the efficiency of this strategy and shortens the lifespan of patients. The exploration of targeted therapy is ongoing in TNBC research. The aim of the present study was to identify the mechanism underlying acquired resistance in TNBC through the exploration of the relationship between the expression of USP7 and of ABCB1. We found that ubiquitin specific protease 7 (USP7) is a potential therapeutic target for overcoming the chemoresistance of TNBC. USP7 overexpression increased the chemoresistance of TNBC, while the knockdown of USP7 effectively increased the chemosensitivity of chemoresistant TNBC. A USP7 inhibitor effectively induced apoptosis and suppressed metastasis in chemoresistant TNBC. We further clarified that USP7 is a specific deubiquitinating enzyme for ABCB1 that plays an essential role in drug resistance. USP7 directly interacted with ABCB1 and regulated its stability. We concluded that USP7 promotes the chemoresistance of TNBC by stabilizing the ABCB1 protein. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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19 pages, 4916 KiB  
Article
The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment
by Domenica Berardi, Yasmin Hunter, Lisa van den Driest, Gillian Farrell, Nicholas J. W. Rattray and Zahra Rattray
Cancers 2022, 14(15), 3661; https://doi.org/10.3390/cancers14153661 - 27 Jul 2022
Cited by 4 | Viewed by 2866
Abstract
Metabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely [...] Read more.
Metabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely to fingerprint the impact of olaparib treatment in cellular metabolism. Here, we report the biomolecular response of breast cancer cell lines with DNA damage repair defects to olaparib exposure. Following evaluation of olaparib sensitivity in breast cancer cell lines, we immunoprobed DNA double strand break foci and evaluated changes in cellular metabolism at various olaparib treatment doses using untargeted mass spectrometry-based metabolomics analysis. Following identification of altered features, we performed pathway enrichment analysis to measure key metabolic changes occurring in response to olaparib treatment. We show a cell-line-dependent response to olaparib exposure, and an increased susceptibility to DNA damage foci accumulation in triple-negative breast cancer cell lines. Metabolic changes in response to olaparib treatment were cell-line and dose-dependent, where we predominantly observed metabolic reprogramming of glutamine-derived amino acids and lipids metabolism. Our work demonstrates the effectiveness of combining molecular biology and metabolomics studies for the comprehensive characterisation of cell lines with different genetic profiles. Follow-on studies are needed to map the baseline metabolism of breast cancer cells and their unique response to drug treatment. Fused with genomic and transcriptomics data, such readout can be used to identify key oncometabolites and inform the rationale for the design of novel drugs or chemotherapy combinations. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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20 pages, 3913 KiB  
Article
Relationship of micro-RNA, mRNA and eIF Expression in Tamoxifen-Adapted MCF-7 Breast Cancer Cells: Impact of miR-1972 on Gene Expression, Proliferation and Migration
by Akhil Behringer, Darko Stoimenovski, Martin Porsch, Katrin Hoffmann, Gerhard Behre, Ivo Grosse, Thomas Kalinski, Johannes Haybaeck and Norbert Nass
Biomolecules 2022, 12(7), 916; https://doi.org/10.3390/biom12070916 - 29 Jun 2022
Cited by 3 | Viewed by 2266
Abstract
Background: Tamoxifen-adapted MCF-7-Tam cells represent an in-vitro model for acquired tamoxifen resistance, which is still a problem in clinics. We here investigated the correlation of microRNA-, mRNA- and eukaryotic initiation factors (eIFs) expression in this model. Methods: MicroRNA- and gene expression were analyzed [...] Read more.
Background: Tamoxifen-adapted MCF-7-Tam cells represent an in-vitro model for acquired tamoxifen resistance, which is still a problem in clinics. We here investigated the correlation of microRNA-, mRNA- and eukaryotic initiation factors (eIFs) expression in this model. Methods: MicroRNA- and gene expression were analyzed by nCounter and qRT-PCR technology; eIFs by Western blotting. Protein translation mode was determined using a reporter gene assay. Cells were transfected with a miR-1972-mimic. Results: miR-181b-5p,-3p and miR-455-5p were up-, miR-375, and miR-1972 down-regulated and are significant in survival analysis. About 5% of the predicted target genes were significantly altered. Pathway enrichment analysis suggested a contribution of the FoxO1 pathway. The ratio of polio-IRES driven to cap-dependent protein translation shifted towards cap-dependent initiation. Protein expression of eIF2A, -4G, -4H and -6 decreased, whereas eIF3H was higher in MCF-7-Tam. Significant correlations between tamoxifen-regulated miRNAs and eIFs were found in representative breast cancer cell lines. Transfection with a miR-1972-mimic reverses tamoxifen-induced expression for a subset of genes and increased proliferation in MCF-7, but reduced proliferation in MCF-7-Tam, especially in the presence of 4OH-tamoxifen. Migration was inhibited in MCF-7-Tam cells. Translation mode remained unaffected. Conclusions: miR-1972 contributes to the orchestration of gene-expression and physiological consequences of tamoxifen adaption. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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13 pages, 404 KiB  
Article
Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer
by Jin Sun Lee, Susan E. Yost, Sierra Min Li, Yujie Cui, Paul H. Frankel, Yate-Ching Yuan, Daniel Schmolze, Colt A. Egelston, Weihua Guo, Mireya Murga, Helen Chang, Linda Bosserman and Yuan Yuan
Cancers 2022, 14(13), 3159; https://doi.org/10.3390/cancers14133159 - 28 Jun 2022
Cited by 5 | Viewed by 2447
Abstract
Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or [...] Read more.
Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6–24 months for 0–1 lines; 6–9 months for ≥2 lines); or late progressors (>24 months for 0–1 lines; >9 months PFS for ≥2 lines). NGS and RNA sequencing data were analyzed in association with PFS, and survival analysis was stratified by prior lines of chemotherapy. A total of 795 patients with HR+ MBC treated with CDK 4/6i were identified. Of these, 144 (18%) patients had genomic data and 29 (3.6%) had RNA data. Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed associations with PFS (p-value ≤ 0.15 and HR ≥ 1.5 or HR < 0.5). Whole transcriptome RNAseq was analyzed for 24/109 (22%) patients with 0–1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). In this retrospective analysis, genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy. Full article
(This article belongs to the Topic Adaptation Mechanisms in Therapy-Resistant Breast Cancer)
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