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9. Supplementary Figure 7 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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10. Data from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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11. Supplementary Figure 4 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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12. Supplementary Methods from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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13. Supplementary Figure 5 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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14. Supplementary Table 1 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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15. Supplementary Figure 6 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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16. Supplementary Figure 3 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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17. Supplementary Figure 1 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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18. Supplementary Figure 2 from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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19. Supplementary Figure Legends from 3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

Author

Onion, David, primary, Argent, Richard H., primary, Reece-Smith, Alexander M., primary, Craze, Madeleine L., primary, Pineda, Robert G., primary, Clarke, Philip A., primary, Ratan, Hari L., primary, Parsons, Simon L., primary, Lobo, Dileep N., primary, Duffy, John P., primary, Atherton, John C., primary, McKenzie, Andrew J., primary, Kumari, Rajendra, primary, King, Peter, primary, Hall, Brett M., primary, and Grabowska, Anna M., primary

Published
2023
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23. SLC1A5 co-expression with TALDO1 associates with endocrine therapy failure in oestrogen receptor-positive breast cancer

Author

Alfarsi, Lutfi H., Ansari, Rokaya El, Craze, Madeleine L., Mohammed, Omar J., Masisi, Brendah K., Ellis, Ian O., Rakha, Emad A., and Green, Andrew R.

Subjects
Nottingham Breast Cancer Research Centre
Abstract

Purpose: Identification of effective biomarkers for the benefit of endocrine treatment and understanding the molecular pathways that contribute to the development of resistance are of crucial importance to the management of luminal breast cancer. The amino acid transporter SLC1A5 has emerging importance as a prognostic marker and potential therapeutic target in various types of cancer. This study aims to investigate its role in luminal breast cancer as a potential predictive marker for endocrine treatment. Methods: SLC1A5 expression was assessed at the transcriptomic and proteomic levels in large, well-characterized cohorts of luminal breast cancer. The sensitivity to endocrine therapy after SLC1A5 knockdown was investigated in vitro, using MCF7 and MDA-MB-175 cell lines. Bioinformatic analyses were performed to study the interacting networks of SLC1A5, and to identify a key co-expressed gene with SLC1A5.Results: here we showed that patients with tumors that highly expressed SLC1A5 associated with a high risk of relapse after endocrine treatment. In vitro, depletion of SLC1A5 increases the sensitivity of luminal breast cancer cells to tamoxifen. TALDO1 was identified as key co-expressed gene with SLC1A5, and in vitro knockdown of SLC1A5 showed reduction in TALDO1 expression. Indeed, TALDO1 was associated with poor clinical outcomes in patients who were subject to endocrine therapy.Conclusion: These findings suggest that metabolic alterations, particularly the interaction between the key amino acid transporter SLC1A5 and metabolic enzyme TALDO1, could affect the sensitivity of endocrine therapy. This study demonstrated the prognostic value of both SLC1A5 and TALDO1 as biomarkers in luminal breast cancer.

Published
2021

26. Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer

Author

Morotti, Matteo, primary, Zois, Christos E., additional, El-Ansari, Rokaya, additional, Craze, Madeleine L., additional, Rakha, Emad A., additional, Fan, Shih-Jung, additional, Valli, Alessandro, additional, Haider, Syed, additional, Goberdhan, Deborah C. I., additional, Green, Andrew R., additional, and Harris, Adrian L., additional

Published
2020
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32. Enhanced glutamine uptake influences composition of immune cell infiltrates in breast cancer

Author

Ansari, Rokaya El, Craze, Madeleine L, Althobiti, Maryam, Alfarsi, Lutfi, Ellis, Ian O, Rakha, Emad A, and Green, Andrew R.

Subjects
Breast cancer, Nottingham Breast Cancer Research Centre, SLC1A5, SLC3A2, SLC7A5, Immune cells infiltrates
Abstract

Background: Cancer cells must alter their metabolism to support proliferation. Immune evasion also plays a role in supporting tumour progression. This study aimed to find whether enhanced glutamine uptake in breast cancer (BC) can derive the existence of specific immune cells subtypes, including the subsequent impact on patient outcome.Method: SLC1A5, SLC7A5, SLC3A2 and immune cell markers; CD3, CD8, FOXP3, CD20 and CD68, in addition to PD1 and PDL1 were assessed using immunohistochemistry on TMAs constructed from a large BC cohort (n=803). Patients were stratified based on SLC protein expression into accredited clusters and correlated with immune cell infiltrates and patient outcome. The effect of transient siRNA knockdown of SLC7A5 and SLC1A5 on PDL1 expression was evaluated in MDA-MB-231 cells.Results: High SLCs were significantly associated with PDL1 and PD1+, FOXP3+, CD68+ and CD20+ cells (p

Published
2019

34. The role of glutaminase in cancer

Author

Masisi, Brendah K, primary, El Ansari, Rokaya, additional, Alfarsi, Lutfi, additional, Rakha, Emad A, additional, Green, Andrew R, additional, and Craze, Madeleine L, additional

Published
2020
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35. Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer

Author

Onion, David, Isherwood, Mark, Shridhar, Naveen, Xenophontos, Mikalena, Craze, Madeleine L., Day, Laura J., Pineda, Robert G., Reece-Smith, Alex M., Saunders, John H., Duffy, John P., Argent, Richard H., and Grabowska, Anna M.

Subjects
Non-Small Cell Lung Cancer, Tumour microenvironment, Caveolin-1, Tenascin-C, T Cell
Abstract

The complex interplay of the tumour microenvironment (TME) and its role in disease progression and response to therapy is poorly understood. The majority of studies to date focus on individual components or molecules within the TME and so lack the power correlative analysis. Here we have performed a multi-parameter analysis of the TME in 62 resectable non-small cell lung cancer (NSCLC) specimens detailing number and location of immune infiltrate, assessing markers of cancer-associated fibroblasts, caveolin-1 and tenascin-C, and correlating with clinicopathological details, as well as markers of disease progression such as epithelial-to-mesenchymal transition (EMT). The influence of individual parameters on overall survival was determined in univariate and multivariate analysis and the combination of risk factors and interplay between components analysed. Low numbers of CD8 T cells, low stromal levels of caveolin-1 or high levels of tenascin-C were significant prognostic markers of decreased overall survival in both univariate and multivariate analysis. Patients with two or more risk factors had dramatically reduced overall survival and those with all three a median survival of just 7.5 months. In addition, low levels of tumour E-cadherin correlated with reduced immune infiltrate into the tumour nests, possibly linking EMT to the avoidance of CD8 T cell control. The multicomponent approach has allowed identification of the dominant influences on overall survival, and exploration of the interplay between different components of the TME in NSCLC.

Published
2018

36. FOXP1 expression correlates with better prognosis in invasive breast cancer including the ER-positive luminal subtype

Author

Joseph, C., Craze, Madeleine L., Nolan, C.C., Diez-Rodriguez, Maria, Green, Andrew R., Rakha, Emad, Ellis, Ian O., and Mukherjee, A.

Abstract

Background: Fork head box P1 (FOXP1) is a FOX family transcription factor influencing ERα;-regulated transcription by interaction with the ERα; related pioneer factor FOXA1. Altered FOXP1 expression is seen in breast and prostate cancers. This study investigated FOXP1 at the protein level in breast cancer (BC) and examined associations with clinicopathological and molecular features.\ud Methods: FOXP1 mRNA expression was investigated in the METABRIC BC cohort (n=1980) and validated using online expression datasets [bc-GenExMiner v4.0]. Protein expression was studied in a well characterised BC primary series (n=621) using immunohistochemistry and correlations made with clinicopathological parameters and outcome.\ud Results: High FOXP1 mRNA and protein expression was significantly associated with low grade, low NPI, positive ER/PR status, lobular BCs, low Ki67 and negative Her2 status (p

Published
2017

37. Glutamate dehydrogenase (GLUD1) expression in breast cancer

Author

Craze, Madeleine L., primary, El-Ansari, Rokaya, additional, Aleskandarany, Mohammed A., additional, Cheng, Kiu Wai, additional, Alfarsi, Lutfi, additional, Masisi, Brendah, additional, Diez-Rodriguez, Maria, additional, Nolan, Christopher C., additional, Ellis, Ian O., additional, Rakha, Emad A., additional, and Green, Andrew R., additional

Published
2018
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38. 3-dimensional patient-derived lung cancer assays reveal resistance to standards-of-care promoted by stromal cells but sensitivity to histone deacetylase inhibitors

Author

Onion, David, Argent, Richard H., Reece-Smith, Alex M., Craze, Madeleine L., Pineda, Robert G., Clarke, Philip A., Ratan, Hari L., Parsons, Simon L., Lobo, Dileep N., Duffy, John P., Atherton, John C., McKenzie, Andrew J., Kumari, Rajendra, King, Peter, Hall, Brett M., and Grabowska, Anna M.

Abstract

There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-passage patient tumor–derived tissue into basement membrane extract, ensuring a low proportion of cell death to anoikis and growth complementation by coculture with patient-derived cancer-associated fibroblasts (CAF). A range of solid tumors proved amenable to growth and pharmacologic testing in this 3D assay. A study of 30 early-stage non–small cell lung cancer (NSCLC) specimens revealed high levels of de novo resistance to a large range of standard-of-care agents, while histone deacetylase (HDAC) inhibitors and their combination with antineoplastic drugs displayed high levels of efficacy. Increased resistance was seen in the presence of patient-derived CAFs for many agents, highlighting the utility of the assay for tumor microenvironment-educated drug testing. Standard-of-care agents showed similar responses in the 3D ex vivo and patient-matched in vivo models validating the 3D-Tumor Growth Assay (3D-TGA) as a high-throughput screen for close-to-patient tumors using significantly reduced animal numbers. Mol Cancer Ther; 15(4); 753–63. ©2016 AACR.

Published
2016

39. MYC regulation of glutamine–proline regulatory axis is key in luminal B breast cancer

Author

Craze, Madeleine L, primary, Cheung, Hayley, additional, Jewa, Natasha, additional, Coimbra, Nuno D M, additional, Soria, Daniele, additional, El-Ansari, Rokaya, additional, Aleskandarany, Mohammed A, additional, Wai Cheng, Kiu, additional, Diez-Rodriguez, Maria, additional, Nolan, Christopher C, additional, Ellis, Ian O, additional, Rakha, Emad A, additional, and Green, Andrew R, additional

Published
2017
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41. Multicomponent analysis of the tumour microenvironment reveals low CD8 T cell number, low stromal caveolin-1 and high tenascin-C and their combination as significant prognostic markers in non-small cell lung cancer

Author

Onion, David, primary, Isherwood, Mark, additional, Shridhar, Naveen, additional, Xenophontos, Mikalena, additional, Craze, Madeleine L., additional, Day, Laura J., additional, García-Márquez, María A., additional, Pineda, Robert G., additional, Reece-Smith, Alexander M., additional, Saunders, John H., additional, Duffy, John P., additional, Argent, Richard H., additional, and Grabowska, Anna M., additional

Published
2017
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42. The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours.

Author

Ansari, Rokaya El, Craze, Madeleine L., Miligy, Islam, Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad A., Green, Andrew R., and El Ansari, Rokaya

Subjects
AMINO acid transport, BREAST cancer prognosis, PROTEOMICS, IMMUNOHISTOCHEMISTRY, MOLECULAR oncology
Abstract

Background: Breast cancer (BC) is a heterogeneous disease characterised by variant biology and patient outcome. The amino acid transporter, SLC7A5, plays a role in BC although its impact on patient outcome in different BC subtypes remains to be validated. This study aimed to determine whether the clinicopathological and prognostic value of SLC7A5 is different within the molecular classes of BC.Methods: SLC7A5 was assessed at the genomic level, using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data (n = 1980), and proteomic level, using immunohistochemical analysis and tissue microarray (TMA) (n = 2664; 1110 training and 1554 validation sets) in well-characterised primary BC cohorts. SLC7A5 expression correlated with clinicopathological and biological parameters, molecular subtypes and patient outcome.Results: SLC7A5 mRNA and protein expression were strongly correlated with larger tumour size and higher grade. High expression was observed in triple negative (TN), human epidermal growth factor receptor 2 (HER2)+, and luminal B subtypes. SLC7A5 mRNA and protein expression was significantly associated with the expression of the key regulator of tumour cell metabolism, c-MYC, specifically in luminal B tumours only (p = 0.001). High expression of SLC7A5 mRNA and protein was associated with poor patient outcome (p < 0.001) but only in the highly proliferative oestrogen receptor (ER)+/ luminal B (p = 0.007) and HER2+ classes of BC (p = 0.03). In multivariate analysis, SLC7A5 protein was an independent risk factor for shorter breast-cancer-specific survival only in ER+ high-proliferation tumours (p = 0.02).Conclusions: SLC7A5 appears to play a role in the aggressive highly proliferative ER+ subtype driven by MYC and could act as a potential therapeutic target. Functional assessment is necessary to reveal the specific role played by this transporter in the ER+ highly proliferative subclass and HER2+ subclass of BC. [ABSTRACT FROM AUTHOR]

Published
2018
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43. Altered glutamine metabolism in breast cancer: subtype dependencies and alternative adaptations

Author

El Ansari, Rokaya, McIntyre, Alan, Craze, Madeleine L., Ellis, Ian O., Rakha, Emad A., and Green, Andrew R.

Subjects
Nottingham Breast Cancer Research Centre, Breast cancer, metabolic pathways, glutamine, molecular classes, skin and connective tissue diseases
Abstract

Cancer cells must alter their metabolism in order to satisfy the demands of necessary energy and cellular building blocks. These metabolic alterations are mediated by many oncogenic changes that affect cellular signalling pathways, which result in sustained cell growth and proliferation. Recently, metabolomics, has received great attention in the field of cancer research and as the essential metabolic pathways that drive tumour growth and progression are determined, the possibilities of new targets for therapeutic intervention are opened. More specifically, as breast cancer is a heterogeneous disease there is growing evidence that differences in metabolic changes exist between molecular subtypes.In this review, the most recent findings in breast cancer cell metabolism are discussed, with particular emphasis on glutamine and its transporters which is considered one of the key amino acids fuelling cancer growth. Furthermore, the metabolic differences between the molecular subtypes of breast cancer are examined, highlighting the clinical utility for breast cancer diagnosis and treatment.

46. The amino acid transporter SLC7A5 confers a poor prognosis in the highly proliferative breast cancer subtypes and is a key therapeutic target in luminal B tumours

Author

El Ansari, Rokaya, Craze, Madeleine L., Miligy, Islam, Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad, Green, Andrew R., El Ansari, Rokaya, Craze, Madeleine L., Miligy, Islam, Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad, and Green, Andrew R.

Abstract

Background: Breast cancer (BC) is a heterogeneous disease characterised by variant biology and patient outcome. The amino acid transporter, SLC7A5, plays a role in BC although its impact on patient outcome in different BC subtypes remains to be validated. This study aimed to determine whether the clinicopathological and prognostic value of SLC7A5 is different within the molecular classes of BC. Methods: SLC7A5 was assessed at the genomic, using METABRIC data (n=1,980), and proteomic, using immunohistochemistry and TMA (n= 2664; 1,110 training and 1,554 validation sets), levels in well-characterised primary BC cohorts. SLC7A5 expression was correlated with clinicopathological and biological parameters, molecular subtypes, and patient outcome. Results: SLC7A5 mRNA and protein expression were strongly correlated with larger tumour size, and higher grade. High expression was observed in triple negative (TN), HER2+, and luminal B subtypes. SLC7A5 mRNA and protein expression was significantly associated with the expression of the key regulator of tumour cell metabolism c-MYC, specifically in Luminal B tumours only (p=0.001). High expression of SLC7A5 mRNA and protein was associated with poor patient outcome (p <0.001) but only in the highly proliferative ER+/ luminal B (p=0.007) and HER2+ classes of BC (p=0.03). In multivariate analysis, SLC7A5 protein was independent risk factor for shorter Breast Cancer Specific Survival only in ER+ high proliferation tumours (p=0.02). Conclusions: SLC7A5 appears to play a role in the aggressive highly proliferative ER+ subtype driven by MYC and could act as a potential therapeutic target. Functional assessment is necessary to reveal the specific role played by this transporter in the ER+highly proliferative subclass and HER2+ subclass of BC.

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47. The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

Author

El Ansari, Rokaya, Craze, Madeleine L., Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad A., Green, Andrew R., El Ansari, Rokaya, Craze, Madeleine L., Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad A., and Green, Andrew R.

Abstract

Background: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity and patient outcome. This study aimed to evaluate the biological and prognostic value of the membrane solute carrier, SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods: SLC3A2 was assessed at the genomic level, using METABRIC data (n=1,980), and proteomic level, using immunohistochemistry on TMA sections constructed from a large well-characterised primary BC cohort (n=2,500). SLC3A2 expression was correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results: SLC3A2 mRNA and protein expression were strongly correlated with higher tumour grade and poor Nottingham prognostic index (NPI). High expression of SLC3A2 was observed in triple negative (TN), HER2+, and ER+ high proliferation subtypes. SLC3A2 mRNA and protein expression were significantly associated with the expression of c-MYC in all BC subtypes (p<0.001). High expression of SLC3A2 protein was associated with poor patient outcome (p<0.001)), but only in the ER+ high proliferation (p=0.01) and triple negative (p=0.04) subtypes. In multivariate analysis SLC3A2 protein was an independent risk factor for shorter breast cancer specific survival (p<0.001). Conclusions: SLC3A2 appears to play a role in the aggressive BC subtypes driven by MYC and could act as a potential prognostic marker. Functional assessment is necessary to reveal its potential therapeutic value in the different BC subtypes.

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48. MYC regulation of Glutamine-Proline regulatory axis is key in Luminal B breast cancer

Author

Craze, Madeleine L., Cheung, Hayley, Jewa, Natasha, Coimbra, Nuno D.M., Soria, Daniele, El-Ansari, Rokaya, Aleskandarany, Mohammed A., Cheng, Kiu Wai, Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad, Green, Andrew R., Craze, Madeleine L., Cheung, Hayley, Jewa, Natasha, Coimbra, Nuno D.M., Soria, Daniele, El-Ansari, Rokaya, Aleskandarany, Mohammed A., Cheng, Kiu Wai, Diez-Rodriguez, Maria, Nolan, Christopher C., Ellis, Ian O., Rakha, Emad, and Green, Andrew R.

Abstract

Background: Altered cellular metabolism is a hallmark of cancer and some are reliant on Glutamine for sustained proliferation and survival. We hypothesise that the Glutamine-Proline regulatory axis has a key role in Breast cancer (BC) in the highly proliferative classes. Methods: Glutaminase (GLS), pyrroline-5-carboxylate synthetase (ALDH18A1) and pyrroline-5-carboxylate reductase 1 (PYCR1) were assessed at DNA/mRNA/protein levels in large well-characterised cohorts. Results: Gain of PYCR1 copy number and high PYCR1 mRNA was associated with luminal B tumours. High ALDH18A1 and high GLS protein expression was observed in the ER+/HER2- high proliferation class (Luminal B) compared with ER+/HER2- low proliferation class (Luminal A) (p=0.030 and p=0.022 respectively), however this was not observed with mRNA. Cluster analysis of the Glutamine-Proline regulatory axis genes revealed significant associations with molecular subtypes of breast cancer and patient outcome independent of standard clinicopathological parameters (p=0.012). High protein expression of the Glutamine-Proline enzymes were all associated with high MYC protein in Luminal B tumours only (p<0.001). Conclusion: We provide comprehensive clinical data indicating that the Glutamine-Proline regulatory axis plays an important role in the aggressive subclass of luminal BC and is therefore a potential therapeutic target.

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50. Phenotypic characterization of breast cancer: the role of CDC42

Author

Chrysanthou, Eleni, Gorringe, Kylie L., Joseph, Chitra, Craze, Madeleine L., Nolan, Christopher C., Diez-Rodriguez, Maria, Green, Andrew R., Rakha, Emad A., Ellis, Ian O., Mukherjee, Abhik, Chrysanthou, Eleni, Gorringe, Kylie L., Joseph, Chitra, Craze, Madeleine L., Nolan, Christopher C., Diez-Rodriguez, Maria, Green, Andrew R., Rakha, Emad A., Ellis, Ian O., and Mukherjee, Abhik

Abstract

Purpose: The molecular landscape of breast cancer (BC), especially of the Luminal A subtype, remains to be fully delineated. Transcriptomic data shows that Luminal A tumours are enriched for aberrant expression of genes in the cell division control 42 homolog (CDC42) pathway. This study aims to investigate protein expression of CDC42 in BC and assess its clinicopathological significance. Methods: Expression of CDC42 protein was examined by immunohistochemistry on tissue microarrays in a well characterised cohort of 895 early stage (I-IIIa) primary invasive BCs. Results: CDC42 expression was observed in both the cytoplasm and nucleus of BC cells. High nuclear CDC42 expression demonstrated a significant correlation with ER positive, low-grade tumours and was more common in the lobular histological subtype (all p<0.001). In contrast, cytoplasmic CDC42 showed increased expression in the ductal subtype (p<0.001) and correlated with negative prognostic features such as larger size, higher grade (p<0.05), and higher Ki67 labelling index (p=0.001). Nuclear CDC42 expression was associated with a longer BC specific survival in all cases (p=0.025) and in luminal ER positive tumours (p=0.011). In multivariate analyses including size, grade, lymph node stage and intrinsic subtype, CDC42 was an independent prognostic factor (p=0.032). Conclusion: The results indicate that CDC42 is important molecule in luminal BC, with prognostic significance.

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