المؤلفون: Timothy J. Peters, Braydon Meyer, Lauren Ryan, Joanna Achinger-Kawecka, Jenny Song, Elyssa M. Campbell, Wenjia Qu, Shalima Nair, Phuc Loi-Luu, Phillip Stricker, Elgene Lim, Clare Stirzaker, Susan J. Clark, Ruth Pidsley

المصدر: BMC Genomics, Vol 25, Iss 1, Pp 1-23 (2024)

مصطلحات موضوعية: DNA methylation, Microarray, EPICv2, WGBS, Validation, Manifest, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background The Illumina family of Infinium Methylation BeadChip microarrays has been widely used over the last 15 years for genome-wide DNA methylation profiling, including large-scale and population-based studies, due to their ease of use and cost effectiveness. Succeeding the popular HumanMethylationEPIC BeadChip (EPICv1), the recently released Infinium MethylationEPIC v2.0 BeadChip (EPICv2) claims to extend genomic coverage to more than 935,000 CpG sites. Here, we comprehensively characterise the reproducibility, reliability and annotation of the EPICv2 array, based on bioinformatic analysis of both manifest data and new EPICv2 data from diverse biological samples. Results We find a high degree of reproducibility with EPICv1, evidenced by comparable sensitivity and precision from empirical cross-platform comparison incorporating whole genome bisulphite sequencing (WGBS), and high correlation between technical sample replicates, including between samples with DNA input levels below the manufacturer’s recommendation. We provide a full assessment of probe content, evaluating genomic distribution and changes from previous array versions. We characterise EPICv2’s new feature of replicated probes and provide recommendations as to the superior probes. In silico analysis of probe sequences demonstrates that probe cross-hybridisation remains a significant problem in EPICv2. By mapping the off-target sites at single nucleotide resolution and comparing with WGBS we show empirical evidence for preferential off-target binding. Conclusions Overall, we find EPICv2 a worthy successor to the previous Infinium methylation microarrays, however some technical issues remain. To support optimal EPICv2 data analysis we provide an expanded version of the EPICv2 manifest to aid researchers in understanding probe design, data processing, choosing appropriate probes for analysis and for integration with methylation datasets from previous versions of the Infinium Methylation BeadChip.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-2164

URL الوصول: https://doaj.org/article/6f52a85a352f46848842385dfa8f78a7

المؤلفون: Leila Hosseinzadeh, Zoya Kikhtyak, Geraldine Laven-Law, Stephen M. Pederson, Caroline G. Puiu, Clive S. D’Santos, Elgene Lim, Jason S. Carroll, Wayne D. Tilley, Amy R. Dwyer, Theresa E. Hickey

المصدر: Genome Biology, Vol 25, Iss 1, Pp 1-28 (2024)

مصطلحات موضوعية: Androgen receptor, GATA3, Breast, Luminal lineage, Biology (General), QH301-705.5, Genetics, QH426-470

الوصف: Abstract Background The androgen receptor (AR) is a tumor suppressor in estrogen receptor (ER) positive breast cancer, a role sustained in some ER negative breast cancers. Key factors dictating AR genomic activity in a breast context are largely unknown. Herein, we employ an unbiased chromatin immunoprecipitation-based proteomic technique to identify endogenous AR interacting co-regulatory proteins in ER positive and negative models of breast cancer to gain new insight into mechanisms of AR signaling in this disease. Results The DNA-binding factor GATA3 is identified and validated as a novel AR interacting protein in breast cancer cells irrespective of ER status. AR activation by the natural ligand 5α-dihydrotestosterone (DHT) increases nuclear AR-GATA3 interactions, resulting in AR-dependent enrichment of GATA3 chromatin binding at a sub-set of genomic loci. Silencing GATA3 reduces but does not prevent AR DNA binding and transactivation of genes associated with AR/GATA3 co-occupied loci, indicating a co-regulatory role for GATA3 in AR signaling. DHT-induced AR/GATA3 binding coincides with upregulation of luminal differentiation genes, including EHF and KDM4B, established master regulators of a breast epithelial cell lineage. These findings are validated in a patient-derived xenograft model of breast cancer. Interaction between AR and GATA3 is also associated with AR-mediated growth inhibition in ER positive and ER negative breast cancer. Conclusions AR and GATA3 interact to transcriptionally regulate luminal epithelial cell differentiation in breast cancer regardless of ER status. This interaction facilitates the tumor suppressor function of AR and mechanistically explains why AR expression is associated with less proliferative, more differentiated breast tumors and better overall survival in breast cancer.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1474-760X

URL الوصول: https://doaj.org/article/d7b51d564a0b4733aace68da8648cf13

المؤلفون: Elysse C. Filipe, Sipiththa Velayuthar, Ashleigh Philp, Max Nobis, Sharissa L. Latham, Amelia L. Parker, Kendelle J. Murphy, Kaitlin Wyllie, Gretel S. Major, Osvaldo Contreras, Ellie T. Y. Mok, Ronaldo F. Enriquez, Suzanne McGowan, Kristen Feher, Lake‐Ee Quek, Sarah E. Hancock, Michelle Yam, Emmi Tran, Yordanos F. I. Setargew, Joanna N. Skhinas, Jessica L. Chitty, Monica Phimmachanh, Jeremy Z. R. Han, Antonia L. Cadell, Michael Papanicolaou, Hadi Mahmodi, Beata Kiedik, Simon Junankar, Samuel E. Ross, Natasha Lam, Rhiannon Coulson, Jessica Yang, Anaiis Zaratzian, Andrew M. Da Silva, Michael Tayao, Ian L. Chin, Aurélie Cazet, Maya Kansara, Davendra Segara, Andrew Parker, Andrew J. Hoy, Richard P. Harvey, Ozren Bogdanovic, Paul Timpson, David R. Croucher, Elgene Lim, Alexander Swarbrick, Jeff Holst, Nigel Turner, Yu Suk Choi, Irina V. Kabakova, Andrew Philp, Thomas R. Cox

المصدر: Advanced Science, Vol 11, Iss 23, Pp n/a-n/a (2024)

مصطلحات موضوعية: biomechanics, breast cancer, extracellular matrix, metabolism, metastasis, Science

الوصف: Abstract In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2198-3844

URL الوصول: https://doaj.org/article/9b5a588e6e1648e795ea8f0708ede5c3

المؤلفون: Leena Karimi, Carla L. Alves, Mikkel G. Terp, Martina Tuttolomondo, Neil Portman, Sidse Ehmsen, Lene E. Johansen, Martin Bak, Elgene Lim, Henrik J. Ditzel

المصدر: Cancer Communications, Vol 43, Iss 6, Pp 720-725 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2523-3548

URL الوصول: https://doaj.org/article/6e1f64b76d404c68a6d355c985622504

المؤلفون: Michael Papanicolaou, Amelia L. Parker, Michelle Yam, Elysse C. Filipe, Sunny Z. Wu, Jessica L. Chitty, Kaitlin Wyllie, Emmi Tran, Ellie Mok, Audrey Nadalini, Joanna N. Skhinas, Morghan C. Lucas, David Herrmann, Max Nobis, Brooke A. Pereira, Andrew M. K. Law, Lesley Castillo, Kendelle J. Murphy, Anaiis Zaratzian, Jordan F. Hastings, David R. Croucher, Elgene Lim, Brian G. Oliver, Fatima Valdes Mora, Benjamin L. Parker, David Gallego-Ortega, Alexander Swarbrick, Sandra O’Toole, Paul Timpson, Thomas R. Cox

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-21 (2022)

مصطلحات موضوعية: Science

الوصف: The distribution and organisation of matrix molecules in the tumour stroma help shape solid tumour progression. Here they perform temporal proteomic profiling of the matrisome during breast cancer progression and show that collagen XII secreted from CAFs provides a pro-invasive microenvironment.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2041-1723

URL الوصول: https://doaj.org/article/9576cecfa4d640e3988d0c14e35ac2b3

المؤلفون: Fiona H. Zhou, Teesha Downton, Allegra Freelander, Joshua Hurwitz, C. Elizabeth Caldon, Elgene Lim

المصدر: Frontiers in Cell and Developmental Biology, Vol 11 (2023)

مصطلحات موضوعية: estrogen receptor, breast cancer, CDK4/6 inhibitor, endocrine therapy, resistance, Biology (General), QH301-705.5

الوصف: CDK4/6 inhibitors have become game-changers in the treatment of estrogen receptor-positive (ER+) breast cancer, and in combination with endocrine therapy are the standard of care first-line treatment for ER+/HER2-negative advanced breast cancer. Although CDK4/6 inhibitors prolong survival for these patients, resistance is inevitable and there is currently no clear standard next-line treatment. There is an urgent unmet need to dissect the mechanisms which drive intrinsic and acquired resistance to CDK4/6 inhibitors and endocrine therapy to guide the subsequent therapeutic decisions. We will review the insights gained from preclinical studies and clinical cohorts into the diverse mechanisms of CDK4/6 inhibitor action and resistance, and highlight potential therapeutic strategies in the context of CDK4/6 inhibitor resistance.

وصف الملف: electronic resource

Relation: https://www.frontiersin.org/articles/10.3389/fcell.2023.1148792/full; https://doaj.org/toc/2296-634X

URL الوصول: https://doaj.org/article/d41e010baccd4a00b62b7cf83e137075

المؤلفون: Joshua Hurwitz, Lucy Roxana Haggstrom, Elgene Lim

المصدر: Pharmaceutics, Vol 15, Iss 8, p 2017 (2023)

مصطلحات موضوعية: antibody–drug conjugate, cancer, clinical trials, Pharmacy and materia medica, RS1-441

الوصف: Antibody–drug conjugates (ADCs) have provided new therapeutic options and significant promise for patients with cancer, particularly where existing treatments are limited. Substantial effort in ADC development is underway globally, with 13 ADCs currently approved and many more in development. The therapeutic benefits of ADCs leverage the ability to selectively target cancer cells through antibody binding, resultant relative sparing of non-malignant tissues, and the targeted delivery of a cytotoxic payload. Consequently, this drug class has demonstrated activity in multiple malignancies refractory to standard therapeutic options. Despite this, limitations exist, including narrow therapeutic windows, unique toxicity profiles, development of therapeutic resistance, and appropriate biomarker selection. This review will describe the development of ADCs, their mechanisms of action, pivotal trials, and approved indications and identify common themes. Current challenges and opportunities will be discussed for this drug class in cancer therapeutics at a time when significant developments in antibody therapies, immunotherapy, and targeted agents are occurring.

وصف الملف: electronic resource

Relation: https://www.mdpi.com/1999-4923/15/8/2017; https://doaj.org/toc/1999-4923

URL الوصول: https://doaj.org/article/496df9916ac749a4ae8a135516943087

المؤلفون: Nicole J. Chew, Terry C. C. Lim Kam Sian, Elizabeth V. Nguyen, Sung-Young Shin, Jessica Yang, Mun N. Hui, Niantao Deng, Catriona A. McLean, Alana L. Welm, Elgene Lim, Peter Gregory, Tim Nottle, Tali Lang, Melissa Vereker, Gary Richardson, Genevieve Kerr, Diana Micati, Thierry Jardé, Helen E. Abud, Rachel S. Lee, Alex Swarbrick, Roger J. Daly

المصدر: Breast Cancer Research, Vol 23, Iss 1, Pp 1-20 (2021)

مصطلحات موضوعية: Targeted therapy, Oncogene, Fibroblast growth factor receptor, SKI proto-oncogene, Precision oncology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1465-542X

URL الوصول: https://doaj.org/article/42109f40f72f49ee97c97e5cf45b49ce

المؤلفون: Carla L. Alves, Sidse Ehmsen, Mikkel G. Terp, Neil Portman, Martina Tuttolomondo, Odd L. Gammelgaard, Monique F. Hundebøl, Kamila Kaminska, Lene E. Johansen, Martin Bak, Gabriella Honeth, Ana Bosch, Elgene Lim, Henrik J. Ditzel

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)

مصطلحات موضوعية: Science

الوصف: CDK4/6 inhibitors in combination with endocrine therapy has shown efficacy in ER + breast cancer patients but resistance can occur. Here, the authors demonstrate that co-targeting CDK4/6 and AKT with endocrine therapy prevents acquired resistance and therapy adaptation.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2041-1723

URL الوصول: https://doaj.org/article/73e69d21bd364412a70101afb76ad7da

المؤلفون: Diar Aziz, Neil Portman, Kristine J. Fernandez, Christine Lee, Sarah Alexandrou, Alba Llop-Guevara, Zoe Phan, Aliza Yong, Ashleigh Wilkinson, C. Marcelo Sergio, Danielle Ferraro, Dariush Etemadmoghadam, David D. Bowtell, kConFab Investigators, Violeta Serra, Paul Waring, Elgene Lim, C. Elizabeth Caldon

المصدر: npj Breast Cancer, Vol 7, Iss 1, Pp 1-14 (2021)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/2374-4677

URL الوصول: https://doaj.org/article/6daf1a428240435b83fc21ea45524a31