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Topic Editors

Prof. Dr. Luisa Alejandra Helguero
Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
Dr. Iola F. Duarte Ciceco
Department of Chemistry, Technological Laboratories, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-093 Aveiro, Portugal
Prof.Dr. Ana M. Gil
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
31 December 2022
Manuscript submission deadline
31 March 2023
Viewed by
6358

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
6.064 5.7 2011 15.8 Days 2100 CHF Submit
Cancers
cancers
6.575 5.8 2009 17.4 Days 2400 CHF Submit
Cells
cells
7.666 6.7 2012 15.7 Days 2200 CHF Submit
Current Oncology
curroncol
3.109 3.5 1994 20.5 Days 1800 CHF Submit
Onco
onco
- - 2021 15.0 days * 1000 CHF Submit

* Median value for all MDPI journals in the first half of 2022.


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Published Papers (6 papers)

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Article
The Clinicopathological Significance of BiP/GRP-78 in Breast Cancer: A Meta-Analysis of Public Datasets and Immunohistochemical Detection
Curr. Oncol. 2022, 29(12), 9066-9087; https://doi.org/10.3390/curroncol29120710 - 23 Nov 2022
Viewed by 526
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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Article
Combination of Immune-Related Network and Molecular Typing Analysis Defines a Three-Gene Signature for Predicting Prognosis of Triple-Negative Breast Cancer
Biomolecules 2022, 12(11), 1556; https://doi.org/10.3390/biom12111556 - 25 Oct 2022
Viewed by 504
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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Article
USP7 Induces Chemoresistance in Triple-Negative Breast Cancer via Deubiquitination and Stabilization of ABCB1
Cells 2022, 11(20), 3294; https://doi.org/10.3390/cells11203294 - 19 Oct 2022
Cited by 1 | Viewed by 589
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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Article
The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment
Cancers 2022, 14(15), 3661; https://doi.org/10.3390/cancers14153661 - 27 Jul 2022
Cited by 1 | Viewed by 1064
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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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
Biomolecules 2022, 12(7), 916; https://doi.org/10.3390/biom12070916 - 29 Jun 2022
Viewed by 990
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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Article
Genomic Markers of CDK 4/6 Inhibitor Resistance in Hormone Receptor Positive Metastatic Breast Cancer
Cancers 2022, 14(13), 3159; https://doi.org/10.3390/cancers14133159 - 28 Jun 2022
Cited by 1 | Viewed by 1095
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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