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1. The role of the ALKBH5 RNA demethylase in invasive breast cancer

Author

Woodcock, Corinne L., Alsaleem, Mansour, Toss, Michael S., Lothion-Roy, Jennifer, Harris, Anna E., Jeyapalan, Jennie N., Blatt, Nataliya, Rizvanov, Albert A., Miftakhova, Regina R., Kariri, Yousif A., Madhusudan, Srinivasan, Green, Andrew R., Rutland, Catrin S., Fray, Rupert G., Rakha, Emad A., and Mongan, Nigel P.

Published
2024
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2. L1-regularized neural ranking for risk stratification and its application to prediction of time to distant metastasis in luminal node negative chemotherapy na\'ive breast cancer patients

Author

Minhas, Fayyaz, Toss, Michael S., Wahab, Noor ul, Rakha, Emad, and Rajpoot, Nasir M.

Subjects
Computer Science - Machine Learning, Statistics - Applications
Abstract

Can we predict if an early stage cancer patient is at high risk of developing distant metastasis and what clinicopathological factors are associated with such a risk? In this paper, we propose a ranking based censoring-aware machine learning model for answering such questions. The proposed model is able to generate an interpretable formula for risk stratifi-cation using a minimal number of clinicopathological covariates through L1-regulrization. Using this approach, we analyze the association of time to distant metastasis (TTDM) with various clinical parameters for early stage, luminal (ER+ or HER2-) breast cancer patients who received endocrine therapy but no chemotherapy (n = 728). The TTDM risk stratification formula obtained using the proposed approach is primarily based on mitotic score, histolog-ical tumor type and lymphovascular invasion. These findings corroborate with the known role of these covariates in increased risk for distant metastasis. Our analysis shows that the proposed risk stratification formula can discriminate between cases with high and low risk of distant metastasis (p-value < 0.005) and can also rank cases based on their time to distant metastasis with a concordance-index of 0.73., Comment: Accepted in proc. (Machine Learning for Pharma and Healthcare Applications PharML 2021) European Conference on Machine Learning and Principles and Practice of Knowledge Discovery in Databases, Sep 13-17, 2021

Published
2021

8. Deciphering the Role of ASPM in Breast Cancer: A Comprehensive Multicohort Study.

Author

Ibrahim, Asmaa, Atallah, Nehal M., Makhlouf, Shorouk, Toss, Michael S., Green, Andrew, and Rakha, Emad

Subjects
BREAST cancer prognosis, PROTEINS, CHROMOSOME structure, RECEIVER operating characteristic curves, CANCER invasiveness, DRUG resistance in cancer cells, RESEARCH funding, CANCER relapse, BREAST tumors, GENETIC markers, TREATMENT effectiveness, GENE expression, LONGITUDINAL method, IMMUNOHISTOCHEMISTRY, ADJUVANT chemotherapy, CYTOPLASM, RESEARCH, DISEASE progression
Abstract

Simple Summary: ASPM is a gene involved in cell division, and recent research shows that it plays an important role in breast cancer (BC). This study looked at large datasets of BC patients to see how ASPM is linked to tumor growth and patient outcomes. We found that patients with higher levels of ASPM had more aggressive forms of cancer and poorer chances of survival. This suggests that ASPM may be useful as a marker to predict how aggressive the BC is and how well it will respond to treatment. These findings could guide future research and potentially lead to new treatments targeting ASPM in cancer. Background: Assembly factor for spindle microtubules (ASPM) has gained significant attention in cancer research due to its association with tumor growth and progression. Through the analysis of large-scale genomic datasets, ASPM has been identified as the top upregulated gene in breast cancer (BC), characterized by high proliferation. This multicohort study aimed to investigate the clinicopathological and prognostic significance of ASPM mRNA and protein expression in BC. Methods: ASPM mRNA expression was assessed using the Cancer Genome Atlas (TCGA) BC cohort and has been further validated in the Molecular Taxonomy of BC International Consortium (METABRIC) (n = 1980), The Uppsala cohort (n = 249), in addition to the combined multicentric cohort (n = 7252). ASPM protein expression was evaluated in a large BC cohort (n = 1300) using immunohistochemistry. The correlations between ASPM expression, clinicopathological parameters, molecular subtypes and outcome were assessed. The response to taxane treatment was compared to the clinical prognosis of ASPM using the ROC plotter. Results: High ASPM mRNA and protein expression were significantly associated with aggressive BC features and poor survival across all cohorts. The association with poor outcomes was maintained in the adjuvant chemotherapy and radio-therapy-treated patients. Responders to taxane treatment showed significantly elevated ASPM levels compared to non-responders. Conclusions: High ASPM expression predicts poor prognosis in BC. It may play a role in treatment resistance within a specific subgroup of patients. Further clinical trials are warranted to explore the potential of ASPM as a target for therapeutic interventions in cancer. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Predictors of pathological complete response to neoadjuvant treatment and changes to post-neoadjuvant HER2 status in HER2-positive invasive breast cancer

Author

Katayama, Ayaka, Miligy, Islam M., Shiino, Sho, Toss, Michael S., Eldib, Karim, Kurozumi, Sasagu, Quinn, Cecily M., Badr, Nahla, Murray, Ciara, Provenzano, Elena, Callagy, Grace, Martyn, Cian, Millican-Slater, Rebecca, Purdie, Colin, Purnell, Dave, Pinder, Sarah E., Oyama, Tetsunari, Shaaban, Abeer M., Ellis, Ian, Lee, Andrew H.S., and Rakha, Emad A.

Published
2021
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11. Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases

Author

Rakha, Emad A., Miligy, Islam M., Quinn, Cecily M., Provenzano, Elena, Shaaban, Abeer M., Marchiò, Caterina, Toss, Michael S., Gallagy, Grace, Murray, Ciara, Walshe, Janice, Katayama, Ayaka, Eldib, Karim, Badr, Nahla, Tanchel, Bruce, Millican-Slater, Rebecca, Purdie, Colin, Purnell, Dave, Pinder, Sarah E., Ellis, Ian O., and Lee, Andrew H. S.

Published
2021
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20. Artificial Intelligence-Based Mitosis Scoring in Breast Cancer: Clinical Application

Author

Ibrahim, Asmaa, primary, Jahanifar, Mostafa, additional, Wahab, Noorul, additional, Toss, Michael S., additional, Makhlouf, Shorouk, additional, Atallah, Nehal, additional, Lashen, Ayat G., additional, Katayama, Ayaka, additional, Graham, Simon, additional, Bilal, Mohsin, additional, Bhalerao, Abhir, additional, Raza, Shan E Ahmed, additional, Snead, David, additional, Minhas, Fayyaz, additional, Rajpoot, Nasir, additional, and Rakha, Emad, additional

Published
2023
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28. Selective Killing of BRCA2-Deficient Ovarian Cancer Cells via MRE11 Blockade

Author

Alblihy, Adel, primary, Ali, Reem, additional, Algethami, Mashael, additional, Ritchie, Alison A., additional, Shoqafi, Ahmed, additional, Alqahtani, Shatha, additional, Mesquita, Katia A., additional, Toss, Michael S., additional, Ordóñez-Morán, Paloma, additional, Jeyapalan, Jennie N., additional, Dekker, Lodewijk, additional, Salerno, Martina, additional, Hartsuiker, Edgar, additional, Grabowska, Anna M., additional, Rakha, Emad A., additional, Mongan, Nigel P., additional, and Madhusudan, Srinivasan, additional

Published
2023
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30. The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer

Author

Metzler, Veronika M., de Brot, Simone, Haigh, Daisy B., Woodcock, Corinne L., Lothion-Roy, Jennifer, Harris, Anna E., Nilsson, Emeli M., Ntekim, Atara, Persson, Jenny L., Robinson, Brian D., Khani, Francesca, Laursen, Kristian B., Gudas, Lorraine J., Toss, Michael S., Madhusudan, Srinivasan, Rakha, Emad, Heery, David M., Rutland, Catrin S., Mongan, Nigel P., Jeyapalan, Jennie N., Metzler, Veronika M., de Brot, Simone, Haigh, Daisy B., Woodcock, Corinne L., Lothion-Roy, Jennifer, Harris, Anna E., Nilsson, Emeli M., Ntekim, Atara, Persson, Jenny L., Robinson, Brian D., Khani, Francesca, Laursen, Kristian B., Gudas, Lorraine J., Toss, Michael S., Madhusudan, Srinivasan, Rakha, Emad, Heery, David M., Rutland, Catrin S., Mongan, Nigel P., and Jeyapalan, Jennie N.

Abstract

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A a

Published
2023
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31. The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer

Author

Metzler, Veronika M., primary, de Brot, Simone, additional, Haigh, Daisy B., additional, Woodcock, Corinne L., additional, Lothion-Roy, Jennifer, additional, Harris, Anna E., additional, Nilsson, Emeli M., additional, Ntekim, Atara, additional, Persson, Jenny L., additional, Robinson, Brian D., additional, Khani, Francesca, additional, Laursen, Kristian B., additional, Gudas, Lorraine J., additional, Toss, Michael S., additional, Madhusudan, Srinivasan, additional, Rakha, Emad, additional, Heery, David M., additional, Rutland, Catrin S., additional, Mongan, Nigel P., additional, and Jeyapalan, Jennie N., additional

Published
2023
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34. Clinical and molecular significance of the RNA m6A methyltransferase complex in prostate cancer

Author

Lothion-Roy, Jennifer, primary, Haigh, Daisy B., additional, Harris, Anna E., additional, Metzler, Veronika M., additional, Alsaleem, Mansour, additional, Toss, Michael S., additional, Kariri, Yousif, additional, Ntekim, Atara, additional, Robinson, Brian D., additional, Khani, Francesca, additional, Gudas, Lorraine J., additional, Allegrucci, Cinzia, additional, James, Victoria H., additional, Madhusudan, Srinivasan, additional, Mather, Melissa, additional, Emes, Richard D., additional, Archer, Nathan, additional, Fray, Rupert G., additional, Rakha, Emad, additional, Jeyapalan, Jennie N., additional, Rutland, Catrin S., additional, Mongan, Nigel P., additional, and Woodcock, Corinne L., additional

Published
2023
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35. EHD2 overexpression promotes tumorigenesis and metastasis in triple-negative breast cancer by regulating store-operated calcium entry

Author

Luan, Haitao, primary, Bielecki, Timothy A, primary, Mohapatra, Bhopal C, primary, Islam, Namista, additional, Mushtaq, Insha, additional, Bhat, Aaqib M, additional, Mirza, Sameer, additional, Chakraborty, Sukanya, additional, Raza, Mohsin, additional, Storck, Matthew D, additional, Toss, Michael S, additional, Meza, Jane L, additional, Thoreson, Wallace B, additional, Coulter, Donald W, additional, Rakha, Emad A, additional, Band, Vimla, additional, and Band, Hamid, additional

Published
2023
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37. A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients

Author

Xu, Qi, primary, Kaur, Jaspreet, additional, Wylie, Dennis, additional, Mittal, Karuna, additional, Li, Hongxiao, additional, Kolachina, Rishab, additional, Aleskandarany, Mohammed, additional, Toss, Michael S., additional, Green, Andrew R., additional, Yang, Jianchen, additional, Yankeelov, Thomas E., additional, Bhattarai, Shristi, additional, Janssen, Emiel A. M., additional, Kong, Jun, additional, Rakha, Emad A., additional, Kowalski, Jeanne, additional, and Aneja, Ritu, additional

Published
2022
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38. The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

Author

Haigh, Daisy B., primary, Woodcock, Corinne L., additional, Lothion-Roy, Jennifer, additional, Harris, Anna E., additional, Metzler, Veronika M., additional, Persson, Jenny L., additional, Robinson, Brian D., additional, Khani, Francesca, additional, Alsaleem, Mansour, additional, Ntekim, Atara, additional, Madhusudan, Srinivasan, additional, Davis, Melissa B., additional, Laursen, Kristian B., additional, Gudas, Lorraine J., additional, Rutland, Catrin S., additional, Toss, Michael S., additional, Archer, Nathan, additional, Bodi, Zsuzsanna, additional, Rakha, Emad A., additional, Fray, Rupert G., additional, Jeyapalan, Jennie N., additional, and Mongan, Nigel P., additional

Published
2022
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39. Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Author

Harris, Anna E., primary, Metzler, Veronika M., additional, Lothion-Roy, Jennifer, additional, Varun, Dhruvika, additional, Woodcock, Corinne L., additional, Haigh, Daisy B., additional, Endeley, Chantelle, additional, Haque, Maria, additional, Toss, Michael S., additional, Alsaleem, Mansour, additional, Persson, Jenny L., additional, Gudas, Lorraine J., additional, Rakha, Emad, additional, Robinson, Brian D., additional, Khani, Francesca, additional, Martin, Laura M., additional, Moyer, Jenna E., additional, Brownlie, Juliette, additional, Madhusudan, Srinivasan, additional, Allegrucci, Cinzia, additional, James, Victoria H., additional, Rutland, Catrin S., additional, Fray, Rupert G., additional, Ntekim, Atara, additional, de Brot, Simone, additional, Mongan, Nigel P., additional, and Jeyapalan, Jennie N., additional

Published
2022
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40. Clinical Validation of EndoPredict in Pre-Menopausal Women with ER-Positive, HER2-Negative Primary Breast Cancer

Author

Constantinidou, Anastasia, primary, Marcou, Yiola, additional, Toss, Michael S., additional, Simmons, Timothy, additional, Bernhisel, Ryan, additional, Hughes, Elisha, additional, Probst, Braden, additional, Meek, Stephanie, additional, Kakouri, Eleni, additional, Georgiou, Georgios, additional, Zouvani, Ioanna, additional, Savvidou, Gabriella, additional, Kuhl, Vanessa, additional, Doedt, Jennifer, additional, Wagner, Susanne, additional, Gutin, Alexander, additional, Slavin, Thomas P., additional, Lanchbury, Jerry S., additional, Kronenwett, Ralf, additional, Ellis, Ian O., additional, and Rakha, Emad A., additional

Published
2022
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41. Upregulation of Cyclin B2 (CCNB2) in breast cancer contributes to the development of lymphovascular invasion

Author

Aljohani, Abrar I, Toss, Michael S, El-Sharawy, Khloud A, Mirza, Sameer, Ball, Graham R, Green, Andrew R, and Rakha, Emad

Subjects
Nottingham Breast Cancer Research Centre
Abstract

Lymphovascular invasion (LVI) is a key step in breast cancer (BC) metastasis. Targeting the molecular drivers of LVI can improve BC patients’ management. However, the underlying molecular mechanisms of LVI are complex and interconnected with various carcinogenesis pathways. This study aimed to identify the key regulatory gene associated with LVI and to investigate its mechanisms of action and prognostic significance. Artificial neural network (ANN) was applied to two large transcriptomic datasets of BC with well-characterised LVI status. Cyclin B2 (CCNB2) was identified in the top genes associated with LVI positivity. In vitro functional assays were carried out to assess the role of CCNB2 in tumour cell behaviour and their interactions with endothelial cells using a panel of BC cell lines. Large annotated BC cohorts were used to assess the clinical and prognostic role of CCNB2 at the transcriptomic and protein levels. Knockdown (KD) of CCNB2 mRNA reduced BC cell migration, inhibited proliferation, blocked the G2/M transition during the cell cycle and increased the number of apoptotic cells. Importantly, KD of CCNB2 reduced BC cell lines adherence and transmigration across endothelial cell lines. High CCNB2 protein expression was independently associated with LVI positivity in addition to other features of aggressive behaviour, including larger tumour size, higher histological grade, hormonal receptor-negativity, and HER2-positivity, and with shorter survival. We conclude that CCNB2 plays a crucial role in LVI development in BC, implying that CCNB2 could confer a promising therapeutic target to inhibit LVI and reduce metastatic events.

Published
2022

42. Exploring anti-androgen therapies in hormone dependent prostate cancer and new therapeutic routes for castration resistant prostate cancer

Author

Harris, Anna E., Metzler, Veronika M., Lothion-Roy, Jennifer, Varun, Dhruvika, Woodcock, Corinne L., Haigh, Daisy B., Endeley, Chantelle, Haque, Maria, Toss, Michael S., Alsaleem, Mansour, Persson, Jenny L., Gudas, Lorraine J., Rakha, Emad, Robinson, Brian D., Khani, Francesca, Martin, Laura M., Moyer, Jenna E., Brownlie, Juliette, Madhusudan, Srinivasan, Allegrucci, Cinzia, James, Victoria H., Rutland, Catrin S., Fray, Rupert G., Ntekim, Atara, de Brot, Simone, Mongan, Nigel P., Jeyapalan, Jennie N., Harris, Anna E., Metzler, Veronika M., Lothion-Roy, Jennifer, Varun, Dhruvika, Woodcock, Corinne L., Haigh, Daisy B., Endeley, Chantelle, Haque, Maria, Toss, Michael S., Alsaleem, Mansour, Persson, Jenny L., Gudas, Lorraine J., Rakha, Emad, Robinson, Brian D., Khani, Francesca, Martin, Laura M., Moyer, Jenna E., Brownlie, Juliette, Madhusudan, Srinivasan, Allegrucci, Cinzia, James, Victoria H., Rutland, Catrin S., Fray, Rupert G., Ntekim, Atara, de Brot, Simone, Mongan, Nigel P., and Jeyapalan, Jennie N.

Abstract

Androgen deprivation therapies (ADTs) are important treatments which inhibit androgen-induced prostate cancer (PCa) progression by either preventing androgen biosynthesis (e.g. abiraterone) or by antagonizing androgen receptor (AR) function (e.g. bicalutamide, enzalutamide, darolutamide). A major limitation of current ADTs is they often remain effective for limited durations after which patients commonly progress to a lethal and incurable form of PCa, called castration-resistant prostate cancer (CRPC) where the AR continues to orchestrate pro-oncogenic signalling. Indeed, the increasing numbers of ADT-related treatment-emergent neuroendocrine-like prostate cancers (NePC), which lack AR and are thus insensitive to ADT, represents a major therapeutic challenge. There is therefore an urgent need to better understand the mechanisms of AR action in hormone dependent disease and the progression to CRPC, to enable the development of new approaches to prevent, reverse or delay ADT-resistance. Interestingly the AR regulates distinct transcriptional networks in hormone dependent and CRPC, and this appears to be related to the aberrant function of key AR-epigenetic coregulator enzymes including the lysine demethylase 1 (LSD1/KDM1A). In this review we summarize the current best status of anti-androgen clinical trials, the potential for novel combination therapies and we explore recent advances in the development of novel epigenetic targeted therapies that may be relevant to prevent or reverse disease progression in patients with advanced CRPC.

Published
2022
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43. The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

Author

Haigh, Daisy B., Woodcock, Corinne L., Lothion-Roy, Jennifer, Harris, Anna E., Metzler, Veronika M., Persson, Jenny L., Robinson, Brian D., Khani, Francesca, Alsaleem, Mansour, Ntekim, Atara, Madhusudan, Srinivasan, Davis, Melissa B., Laursen, Kristian B., Gudas, Lorraine J., Rutland, Catrin S., Toss, Michael S., Archer, Nathan, Bodi, Zsuzsanna, Rakha, Emad A., Fray, Rupert G., Jeyapalan, Jennie N., Mongan, Nigel P., Haigh, Daisy B., Woodcock, Corinne L., Lothion-Roy, Jennifer, Harris, Anna E., Metzler, Veronika M., Persson, Jenny L., Robinson, Brian D., Khani, Francesca, Alsaleem, Mansour, Ntekim, Atara, Madhusudan, Srinivasan, Davis, Melissa B., Laursen, Kristian B., Gudas, Lorraine J., Rutland, Catrin S., Toss, Michael S., Archer, Nathan, Bodi, Zsuzsanna, Rakha, Emad A., Fray, Rupert G., Jeyapalan, Jennie N., and Mongan, Nigel P.

Abstract

Simple Summary Prostate cancer is driven by androgen receptor-regulated transcription and is a leading cause of cancer deaths. For this reason, androgen deprivation therapies are commonly used to treat advanced prostate cancer. These treatments are often effective for short durations before the emergence of treatment resistance and disease progression to castrate resistant prostate cancer or neuroendocrine-like disease. The aim of this study was to address whether new therapies targeting the epitranscriptome may suppress androgen signalling and thus represent a novel approach to prostate cancer treatment. Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.

Published
2022
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44. Oestrogen-regulated protein SLC39A6: a biomarker of good prognosis in luminal breast cancer

Author

Althobiti, Maryam, El-Sharawy, Khloud A., Joseph, Chitra, Aleskandarany, Mohammed, Toss, Michael S., Green, Andrew R., and Rakha, Emad A.

Subjects
Nottingham Breast Cancer Research Centre
Abstract

PurposeThe outcome of the luminal oestrogen receptor-positive (ER +) subtype of breast cancer (BC) is highly variable and patient stratification needs to be refined. We assessed the prognostic significance of oestrogen-regulated solute carrier family 39 member 6 (SLC39A6) in BC, with emphasis on ER + tumours.Materials and methodsSLC39A6 mRNA expression and copy number alterations were assessed using the METABRIC cohort (n = 1980). SLC39A6 protein expression was evaluated in a large (n = 670) and annotated series of early-stage (I–III) operable BC using tissue microarrays and immunohistochemistry. The associations between SLC39A6 expression and clinicopathological parameters, patient outcomes and other ER-related markers were evaluated using Chi-square tests and Kaplan–Meier curves.ResultsHigh SLC39A6 mRNA and protein expression was associated with features characteristic of less aggressive tumours in the entire BC cohort and ER + subgroup. SLC39A6 protein expression was detected in the cytoplasm and nuclei of the tumour cells. High SLC39A6 nuclear expression and mRNA levels were positively associated with ER + tumours and expression of ER-related markers, including the progesterone receptor, forkhead box protein A1 and GATA binding protein 3. In the ER + luminal BC, high SLC39A6 expression was independently associated with longer BC-specific survival (BCSS) (P = 0.015, HR 0.678, 95% CI 0.472‒0.972) even in those who did not receive endocrine therapy (P = 0.001, HR 0.701, 95% CI 0.463‒1.062).ConclusionSLC39A6 may be prognostic for a better outcome in ER + luminal BC. Further functional studies to investigate the role of SLC39A6 in ER + luminal BC are warranted.

Published
2021

46. Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4

Author

Mittal, Karuna, primary, Kaur, Jaspreet, additional, Sharma, Shaligram, additional, Sharma, Nivya, additional, Wei, Guanhao, additional, Choudhary, Ishita, additional, Imhansi-Jacob, Precious, additional, Maganti, Nagini, additional, Pawar, Shrikant, additional, Rida, Padmashree, additional, Toss, Michael S., additional, Aleskandarany, Mohammed, additional, Janssen, Emiel A., additional, Søiland, Håvard, additional, Gupta, Meenakshi. V., additional, Reid, Michelle D., additional, Rakha, Emad A., additional, and Aneja, Ritu, additional

Published
2021
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49. The prognostic significance of Interferon Stimulated Gene 15 (ISG15) in invasive breast cancer

Author

Kariri, Yousif, Alsaleem, Mansour, Joseph, Chitra, Alsaeed, Sami, Aljohani, Abrar, Shiino, Sho, Toss, Michael S, Green, Andrew R, Rakha, Emad A, and Mohammed, OmarJ.

Subjects
Nottingham Breast Cancer Research Centre
Abstract

BackgroundLymphovascular invasion (LVI) is a prognostic factor in early-stage invasive breast cancer (BC). Through bioinformatics, data analyses of multiple BC cohorts revealed the positive association between interferon-stimulated gene 15 (ISG15) LVI status. Thus, we explored the prognostic significance of ISG15 in BC.MethodsThe prognostic significance of ISG15 mRNA was assessed in METABRIC (n = 1980), TCGA (n = 854) and Kaplan–Meier Plotter (n = 3951). ISG15 protein was evaluated using immunohistochemistry (n = 859) in early-stage invasive BC patients with long-term follow-up. The associations between ISG15 expression and clinicopathological features, expression of immune cell markers and patient outcome data were evaluated.ResultsHigh mRNA and protein ISG15 expression were associated with LVI, higher histological grade, larger tumour size, hormonal receptor negativity, HER2 positivity, p53 and Ki67. High ISG15 protein expression was associated with HER2-enriched BC subtypes and immune markers (CD8, FOXP3 and CD68). High ISG15 mRNA and ISG15 expressions were associated with poor patient outcome. Cox proportional multivariate analysis revealed that the elevated ISG15 expression was an independent prognostic factor of shorter BC-specific survival.ConclusionThis study provides evidence for the role of ISG15 in LVI development and BC prognosis. Further functional studies in BC are warranted to evaluate the therapeutic potential of ISG15.

Published
2021

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