• A Braf kinase-inactive mutant induces lung adenocarcinoma.

      Nieto, P; Ambrogio, C; Esteban-Burgos, L; Gómez-López, G; Blasco, M; Yao, Z; Marais, Richard; Rosen, N; Chiarle, R; Pisano, D; et al. (2017-08-10)
      The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.
    • Brain tumours and the occurrence of severe invasive basal cell carcinoma in first degree relatives with Gorlin syndrome.

      Evans, D Gareth R; Birch, Jillian M; Orton, Clive I; CRC Department of Cancer Genetics, Paterson Institute for Cancer Research, Manchester, UK. (1991)
      We describe the occurrence of a medulloblastoma and an astrocytoma in successive generations of a family with the Gorlin syndrome. The appearance of thousands of invasive basal cell carcinomata after craniospinal irradiation led to the death of one patient from intracranial involvement.
    • BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives.

      Lalloo, Fiona; Varley, Jennifer; Moran, Anthony; Ellis, David; O'Dair, Lindsay; Pharoah, Paul; Antoniou, Antonis; Hartley, Roger; Shenton, Andrew; Seal, Sheila; et al. (2006-05)
      Pathological mutations in BRCA1, BRCA2 and TP53 are associated with an increased risk of breast cancer. This study evaluated mutation frequency of these genes in early-onset breast cancer patients, and correlated this with family history and determined relative risks to family members. Patients with breast adenocarcinoma diagnosed 30 years were ascertained between 1980 and 1997. Family history was established and mutation screening of BRCA1, BRCA2 and TP53 genes was performed. Estimates of penetrance and relative risk were undertaken. DNA was obtained from 100/139 women. 17/36 familial cases had a BRCA1, BRCA2 or TP53 mutation. Of 64 non-familial cases, one BRCA2, two BRCA1 and two TP53 mutations were detected. Penetrance estimates (by age 70) for breast cancer were 84% for BRCA1 mutations and 91% for BRCA2 mutations and for ovarian cancer, 60% and 26%, respectively. Relative risks associated with mutations were consistent with previous studies. BRCA1 and BRCA2 mutations in patients with breast cancer 30 years are predicted strongly by family history. The majority of families with ovarian cancer were due to mutations in BRCA1/2 whereas these mutations only accounted for 30-50% of the excess breast cancers.
    • Breast cancer cells and PD-1/PD-L1 blockade upregulate the expression of PD-1, CTLA-4, TIM-3 and LAG-3 immune checkpoints in CD4(+) T cells

      Saleh, R; Toor, SM; Khalaf, S; Elkord, Eyad; Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha 34110, Qatar (2019)
    • Breast cancer diagnosis, patterns of care and burden of disease in Queensland, Australia (1998-2004): does being Indigenous make a difference?

      Moore, S; Soerjomataram, I; Green, Adèle C; Garvey, G; Martin, J; Valery, P; Division of Epidemiology and Health Systems, Menzies School of Health Research, Charles Darwin University, Level 1/147 Wharf Street, Brisbane Adelaide Street, Spring Hill, PO Box 10639, Brisbane, QLD, 4000, Australia (2015-10-01)
      We compared patterns of care, comorbidity, disability-adjusted life-years (DALYs) and survival in Indigenous and non-Indigenous women with breast cancer in Queensland, Australia (1998-2004).
    • Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study

      Dave, R. V.; Kim, B.; Courtney, A.; O'Connell, R.; Rattay, T.; Taxiarchi, V. P.; Kirkham, J. J.; Camacho, E. M.; Fairbrother, P.; Sharma, N.; et al. (2021)
      Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.
    • Breast cancer stem cells and their role in resistance to endocrine therapy.

      O'Brien, Ciara S; Farnie, Gillian; Howell, Sacha J; Clarke, Robert B; School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK. (2011-04)
      Developmentally, tumours can be viewed as aberrant versions of normal tissues. For example, tumours often retain differentiation markers of their tissue of origin. In addition, there is evidence that they contain cancer stem-like cells (CSCs) that drive tumourigenesis. In this review, we summarise current evidence that breast CSCs may partially explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly oestrogen receptor-α-negative (ER-). If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ER and can only respond to treatment by virtue of paracrine signalling from neighbouring, differentiated ER+ tumour cells. Normal breast epithelial stem cells are regulated by the epidermal growth factor receptor and other growth factor receptor signals. The observed increase in growth factor receptor expression in endocrine-resistant breast cancers may reflect a bigger proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ER- and EGR+/HER2+, which would support this view. It is reported that CSCs express mesenchymal genes, which are suppressed by ER expression, further indicating the mutual exclusion between ER+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ER in these cells in diverse breast tumour sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.
    • Breast cancer stem cells: something out of notching?

      Harrison, Hannah; Farnie, Gillian; Brennan, K; Clarke, Robert B; Breast Biology Group, School of Cancer and Enabling Sciences, Paterson Institute for Cancer Research, University of Manchester;, Manchester, United Kingdom. (2010-11-15)
      We and others have established that the developmental Notch receptor signaling pathway is active in breast cancer cell lines, as well as in preinvasive and invasive primary samples. Recently, a role for Notch in regulating the hierarchy of stem and progenitor cells in both normal and cancer epithelium has been elucidated. Because inhibiting the Notch receptor signaling pathway is a possible future breast cancer therapy, here, we review the expression and activity of the different ligands and receptors and summarize the various ways in which the pathway's activity can be inhibited, and the likely effects of inhibition on different tumor cell subpopulations.
    • Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion

      Shaker, Hudhaifah; Bundred, Nigel J; Landberg, G; Pritchard, SA; Albadry, H; Nicholson, SL; Harries, LJ; Heah, JYE; Castle, John; Kirwan, Cliona C; et al. (2020)
      BACKGROUND: Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS). METHODS: In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival. RESULTS: Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ? .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (?3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT. CONCLUSION: This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.
    • The breast cancer trainees research collaborative group

      Copson, E; Cole, C; Kirwan, Cliona C; McIntosh, S; Palmieri, C; Rea, D; Cancer Sciences Academic Unit, University of Southampton, Somers Cancer Sciences Building, Southampton General Hospital, Southampton, (2020)
    • Breast stem cells and cancer.

      Farnie, Gillian; Clarke, Robert B; Breast Biology Group, School of Cancer and Imaging Sciences, Faculty of Medicine and Human Sciences, University of Manchester, Paterson Institute for Cancer Research, Wilmslow Road, M20 4BX Manchester, UK. (2006)
      Recent results have increased our understanding of normal stem cells and the signalling pathways which regulate them during the development of the mammary gland. Tumours in many tissues are now thought to develop from dysregulated stem cells and depend on activated stem cell self-renewal pathways such as Notch for their tumourigenic capacity. These cancer stem cells are recognised by specific cell surface proteins that they express and their capacity to grow tumours in vivo or spheres in vitro. We have described human breast DCIS mammospheres grown from cancer stem cells and demonstrated their dependence on the EGF and Notch receptor pathways. Stem cell self-renewal pathways such as these may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.
    • Breast tumour stroma is a prognostic indicator and target for therapy.

      Howell, Anthony; Landberg, G; Bergh, J; Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, University of Manchester, The Christie NHS Foundation Trust, University Hospital of South Manchester, Manchester M20 4BX, UK. Anthony.Howell@christie.nhs.uk (2009)
    • Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study.

      Pro, B; Advani, R; Brice, P; Bartlett, N; Rosenblatt, J; Illidge, Timothy M; Matous, J; Ramchandren, R; Fanale, M; Connors, J; et al. (2012-06-20)
      PURPOSE Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL. PATIENTS AND METHODS Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review. Results Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events in ≥ 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%). CONCLUSION Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL. Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy.
    • Bridging the divide:the adjustment and decision making experiences of people with dementia living with a diagnosis of cancer and its impact on family carers

      McWilliams, Lorna; Swarbrick, C; Yorke, Janelle; Farrell, Carole; Grande, G; Bellhouse, Sarah; Keady, J; Christie Patient Centred Research, School of Oncology, The Christie NHS Foundation Trust, Manchester (2020)
    • British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021

      Nasr, I.; McGrath, E. J.; Harwood, C. A.; Botting, J.; Buckley, P.; Budny, P. G.; Fairbrother, P.; Fife, K.; Gupta, G.; Hashme, M.; et al. (2021)
      The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of basal cell carcinoma (BCC). The document aims to: offer an appraisal of all relevant literature up to 24th January 2020 focusing on any key developments address important, practical clinical questions relating to the primary guideline objective provide guideline recommendations and if appropriate research recommendations.
    • Brr6 drives the Schizosaccharomyces pombe spindle pole body nuclear envelope insertion/extrusion cycle.

      Tamm, T; Grallert, Agnes; Grossman, Emily P S; Alvarez-Tabares, Isabel; Stevens, Frances E; Hagan, Iain M; Cancer Research UK Cell Division Group, Paterson Institute for Cancer Research, Manchester M20 4BX, England, UK. (2011-10-31)
      The fission yeast interphase spindle pole body (SPB) is a bipartite structure in which a bulky cytoplasmic domain is separated from a nuclear component by the nuclear envelope. During mitosis, the SPB is incorporated into a fenestra that forms within the envelope during mitotic commitment. Closure of this fenestra during anaphase B/mitotic exit returns the cytoplasmic component to the cytoplasmic face of an intact interphase nuclear envelope. Here we show that Brr6 is transiently recruited to SPBs at both SPB insertion and extrusion. Brr6 is required for both SPB insertion and nuclear envelope integrity during anaphase B/mitotic exit. Genetic interactions with apq12 and defective sterol assimilation suggest that Brr6 may alter envelope composition at SPBs to promote SPB insertion and extrusion. The restriction of the Brr6 domain to eukaryotes that use a polar fenestra in an otherwise closed mitosis suggests a conserved role in fenestration to enable a single microtubule organizing center to nucleate both cytoplasmic and nuclear microtubules on opposing sides of the nuclear envelope.
    • Bryostatin 1 induces productive Epstein-Barr virus replication in latently infected cells: implications for use in immunocompromised patients.

      Stewart, James P; McGown, Alan T; Prendiville, Joseph A; Pettit, G R; Fox, Brian W; Arrand, John R; CRC Department of Molecular Biology, Paterson Institute for Cancer Research, Christie CRC Cancer Centre, Manchester, UK. (1993)
      Bryostatin 1 is a novel anti-tumor agent currently undergoing clinical trial. We investigated the effect of this drug on B-lymphocyte cell lines that carry the Epstein-Barr virus and found that it induces these latently infected cells into the production of transforming virus particles over a wide range of concentrations. These results may have clinical implications, particularly with regard to the use of the drug in the immunocompromised patient.
    • Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro.

      McGown, Alan T; Jayson, Gordon C; Pettit, G R; Haran, M S; Ward, Timothy H; Crowther, Derek; Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK. (1998)
      This study shows that combinations of bryostatin 1, a novel modulator of protein kinase C currently under clinical evaluation, with the anti-oestrogenic agent tamoxifen caused a large synergistic enhancement of growth inhibition in P388 cells in vitro. The growth-inhibitory effects of bryostatin 1 in the presence of non-inhibitory concentrations of tamoxifen were increased by approximately 200-fold, whereas growth inhibition by tamoxifen in the presence of non-inhibitory concentrations of bryostatin 1 were increased over 30-fold. These data have been confirmed by isobologram analysis. The precise mechanism underlying this effect is unknown, although preliminary data implicating protein kinase C is presented. The magnitude of this synergistic effect, together with evidence of clinical responses seen when these agents were given sequentially in ovarian cancer, merits further study.
    • BsmI polymorphism in N-ras intron I (RASN).

      Heighway, Jim; Department of Cancer Genetics, Christie Hospital, Manchester, UK. (1991-02-11)
    • Building a double hexamer of DNA helicase at eukaryotic replication origins.

      Labib, Karim; Cell Cycle group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. klabib@picr.man.ac.uk (2011-12-14)