Emad A Rakha

University of Nottingham, Nottigham, England, United Kingdom

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Publications (205)1042.83 Total impact

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    ABSTRACT: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase 1 (PAK1). PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis. PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n = 980 and 1108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting. We demonstrate that focal genomic amplification and over-expression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P = 1.29 x 10(-4) and P = 0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis. Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.
    Breast cancer research: BCR 04/2015; 17(1):59. DOI:10.1186/s13058-015-0564-5 · 5.88 Impact Factor
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    ABSTRACT: FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14-1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99-1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.
    Oncotarget 04/2015; · 6.63 Impact Factor
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    British Journal of Cancer 03/2015; DOI:10.1038/bjc.2015.115 · 4.82 Impact Factor
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    ABSTRACT: Background: Acinic cell carcinoma (AciCC) is a rare salivary gland-type tumor of the breast, displaying serous acinar differentiation. Despite its triple-negative phenotype, AciCCs are reported to have an indolent clinical behavior. We sought to investigate whether breast AciCCs would be underpinned by genetic alterations found in 254 breast cancer-related genes, and to define whether AciCCs would have a mutational repertoire distinct from that of other triple-negative breast cancers (TNBCs). Design: Three pure and seven mixed breast AciCCs (six AciCC-invasive ductal carcinomas of no special type and one AciCC-metaplastic carcinoma) were included in this study. DNA was extracted from microdissected formalin-fixed paraffin-embedded sections of tumor and normal tissue. In mixed cases each component was microdissected separately. DNA of sufficient quantity was obtained from 2 pure AciCCs, from the AciCC component of 7 mixed cases and from the non-AciCC components of 4 cases. Massively parallel capture sequencing targeting all exons of the 254 genes most frequently mutated in breast cancer was performed. Single nucleotide variants, and insertions and deletions were detected by MuTect, Strelka and VarScan2. Copy number alterations (CNAs) were identified using VarScan2 and GISTIC2.0. Results: Two pure AciCCs and AciCC components from five mixed cases harbored somatic TP53 mutations. One of the TP53 wild-type cases carried a mutation and loss of heterozygosity of MLH1, in addition to somatic mutations in RB1, NF2 and ATR. Additional somatic mutations affecting breast cancer-related genes found in AciCCs included PIK3CA, MTOR, CTNNB1, BRCA1, ERBB4, ERBB3, INPP4B and FGFR2. CNA analysis revealed complex patterns of gains and losses similar to those of TNBCs. Of the 4 mixed cases analyzed, identical somatic mutations were found in the AciCC and non-AciCC component of 2 cases (4 and 7 mutations in common in each case), however additional somatic mutations were identified in the non-AciCC component. In the mixed cases lacking somatic mutations in common, similar patterns of gene CNAs were found in both components of one case. Conclusions: Breast AciCCs display genomic features similar to those reported in TNBCs, harboring complex CNA profiles and TP53 mutations as the most common genetic event. AciCCs may constitute the substrate for the development of more aggressive forms of TNBCs. Category: Breast Pathology
    2015 USCAP Annual Meeting; 03/2015
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    ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARγ) is an adopted orphan receptor that belongs to the nuclear receptor superfamily of transcription factors. PPARγ is regarded as a differentiation factor and it plays an important role in regulating adipogenesis, cell growth, proliferation and tumour progression. In breast cancer (BC), PPARγ agonists were reported to inhibit proliferation and growth invasion and promote phenotypic changes associated with a less malignant and more differentiated status. This study aims to assess the prognostic and biological roles of PPARγ protein expression in a large cohort of BC patients (n = 1100) with emphasis on the luminal oestrogen receptor (ER) positive class. Immunohistochemistry was used to assess the levels of PPARγ expression in BC series prepared as tissue microarrays (TMAs). PPARγ antibody specificity was confirmed using Western blotting. PPARγ nuclear expression was detected in 79 % of the cases and its expression was positively correlated with the hormonal receptors (ER, progesterone receptor and androgen receptor). PPARγ levels were significantly higher in tumours with lobular subtype, smaller size and lower grade, while HER2-positive, ductal or medullary tumours were associated with lower PPARγ levels. Survival analysis showed that PPARγ is associated with better outcome in the whole series as well as in luminal ER-positive class. Cox regression model showed that PPARγ is an independent predictor of outcome. Higher PPARγ was associated with longer survival in patients with ER-positive tumours who did not receive hormone therapy. PPARγ is a good prognostic marker associated with hormone receptors. In patients with luminal BCs, PPARγ is a marker of better prognosis and is associated with longer survival.
    Breast Cancer Research and Treatment 03/2015; DOI:10.1007/s10549-015-3348-9 · 4.20 Impact Factor
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    ABSTRACT: The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily of transcription factors, which exerts anti-proliferative and anti-apoptotic activities. The GR is expressed in a large proportion of breast cancer (BC) although levels generally decrease during cancer progression. This study aimed to determine the clinical and biological significance of GR expression using a large series of early-stage BC with long-term follow-up and BC cell lines. Immunohistochemistry was used to assess the expression of GR in 999 cases of primary invasive BC prepared as tissue microarrays. Reverse phase protein microarray was used to assess the expression of GR in MCF7 and MDA-MB-231 cell lines. Nuclear expression of GR was observed in 61.6 % of breast tumours and was associated with features of good prognosis including smaller tumour size and lower grade with less pleomorphism and low mitotic count. GR expression was positively correlated with expression of oestrogen (ER) and progesterone receptors. In ER-positive tumours, GR was associated with other features of favourable outcome including FOXA1, GATA3 and BEX1 expression, while low GR expression was associated with high Ki67, p53 and CD71 expression. GR expression is associated with features of good outcome but does not provide prognostic information independent of size, stage and grade. Understanding the receptor and its effects on BC behaviour is essential for avoiding any unwanted effects from the use of glucocorticoids in routine oncology practice.
    Breast Cancer Research and Treatment 03/2015; 150(2). DOI:10.1007/s10549-015-3335-1 · 4.20 Impact Factor
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    Journal of Clinical Oncology 03/2015; 33(11). DOI:10.1200/JCO.2014.59.7211 · 17.88 Impact Factor
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    ABSTRACT: Accuracy of core needle biopsy in determining histological grade and type of primary breast cancer in older women MA Albanghali1, MA Aleskandarany1, BM Syed1, AR Green1, EA Rakha1, IO Ellis1 & KL Cheung1 1School of Medicine, University of Nottingham, UK Background: Core needle biopsy (CNB) is currently the standard diagnostic method of breast cancer that forms the basis of subsequent therapeutic strategies, including neo-adjuvant, primary and/or adjuvant therapy. This study aimed to investigate the accuracy of CNB in determining histological grade and type in older women with primary breast cancer. methods: Of a consecutive series of 1,758 women diagnosed at ≥70 years with operable (<5 cm) primary breast cancer, those who underwent primary surgery and with histological grade (Elston/Ellis modification of Bloom and Richardson system) and type (WHO criteria) available from the pathology reports of both CNB and surgical specimens were retrospectively reviewed. Results: Of the 332 patients with grade available, 53%, 61% and 93% of grade 1, 2 and 3 CNBs respectively were shown to have the same grade in the surgical specimens. 6% of grade 1 CNBs were reported as grade 3 in the surgical specimens. None of grade 3 cases (CNB) were reported as grade 1 at surgery. Of the 667 patients with type available, 75%, 64% and 55% reported as invasive ductal (no special type [NST]), lobular carcinoma and ductal carcinoma in situ respectively on CNBs were shown to have the same type in the surgical specimens. Discussion: A high concordance between CNB and surgical specimens has been demonstrated in this older population, notably in grade 3 tumours and with the common histological type (ductal NST). The fact that grade 1 tumours based on CNB seldom turned out to be grade 3 (and vice versa) is also reassuring.
    Third Symposium on Primary Breast Cancer in Older Women; 03/2015
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    ABSTRACT: Accuracy of core needle biopsy in determining histological grade and type of primary breast cancer in older women MA Albanghali1, MA Aleskandarany1, BM Syed1, AR Green1, EA Rakha1, IO Ellis1 & KL Cheung1 1School of Medicine, University of Nottingham, UK Background: Core needle biopsy (CNB) is currently the standard diagnostic method of breast cancer that forms the basis of subsequent therapeutic strategies, including neo-adjuvant, primary and/or adjuvant therapy. This study aimed to investigate the accuracy of CNB in determining histological grade and type in older women with primary breast cancer. methods: Of a consecutive series of 1,758 women diagnosed at ≥70 years with operable (<5 cm) primary breast cancer, those who underwent primary surgery and with histological grade (Elston/Ellis modification of Bloom and Richardson system) and type (WHO criteria) available from the pathology reports of both CNB and surgical specimens were retrospectively reviewed. Results: Of the 332 patients with grade available, 53%, 61% and 93% of grade 1, 2 and 3 CNBs respectively were shown to have the same grade in the surgical specimens. 6% of grade 1 CNBs were reported as grade 3 in the surgical specimens. None of grade 3 cases (CNB) were reported as grade 1 at surgery. Of the 667 patients with type available, 75%, 64% and 55% reported as invasive ductal (no special type [NST]), lobular carcinoma and ductal carcinoma in situ respectively on CNBs were shown to have the same type in the surgical specimens. Discussion: A high concordance between CNB and surgical specimens has been demonstrated in this older population, notably in grade 3 tumours and with the common histological type (ductal NST). The fact that grade 1 tumours based on CNB seldom turned out to be grade 3 (and vice versa) is also reassuring.
    Third Symposium on Primary Breast Cancer in Older Women, Tha University of Nottingham; 03/2015
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    ABSTRACT: The mammalian target of rapamycin complex 1 (mTORC1) is a downstream of the PI3K/Akt pathway which affects cancer development. mTORC1 has many downstream signalling effectors that can enhance different cellular responses. This study aims to investigate the expression of mTORC1 in breast cancer (BC) and correlate it with key clinicopathological and molecular features of BC especially to proteins related to oestrogen receptor (ER) and HER2 pathways in different BC classes. Moreover, mTORC1 expression was assessed in 6 BC cell lines including ER+ and ER- cell lines with and without HER2 transfection. Immunohistochemistry was used to assess the expression of phospho (p) mTORC1 in a large (n = 1300) annotated BC series prepared as tissue microarray. Reverse phase protein array (RPPA) was used to assess its expression in the different BC cell lines. The expression of p-mTORC1 was cytoplasmic with moderate/high expression noted in 44 % of BC. p-mTORC1 expression was associated with clinicopathological variables characteristic of good prognosis. Positive correlation with ER, ER-related proteins AKT, PI3K and luminal differentiation markers were observed in the whole series and in the ER+HER2- subgroup. Association with HER2 was mainly observed in the ER-negative class. RPPA indicated that p-mTORC1 expression was mainly related to ER expression and with better outcome in the Akt positive tumours. p-mTORC1 is associated with good prognostic features. Its expression is related to ER and ER related proteins in addition to AKT and PI3K. Its relation with HER2 expression is mainly seen in the absence of ER expression.
    Breast Cancer Research and Treatment 02/2015; DOI:10.1007/s10549-015-3308-4 · 4.20 Impact Factor
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    ABSTRACT: Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA-associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non-cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC. Electronic supplementary material The online version of this article (doi:10.1007/s10549-015-3306-6) contains supplementary material, which is available to authorized users.
    Breast Cancer Research and Treatment 02/2015; 150(1). DOI:10.1007/s10549-015-3306-6 · 4.20 Impact Factor
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    ABSTRACT: Aims Acinic cell carcinomas (AcCC) of the breast have been reported to constitute the breast counterpart of salivary gland AcCCs, based on the similarities of their histologic and immunohistochemical features. Breast AcCC is a vanishingly rare form of triple-negative breast cancer (TNBC). Recent studies have demonstrated that in TNBCs, the two driver genes most frequently mutated are TP53 (82%) and PIK3CA (10%). We sought to define whether breast AcCCs would harbor TP53 and PIK3CA somatic mutations, and if so, whether these would be present in salivary gland AcCCs. Methods and Results Sanger sequencing of the entire coding region of TP53 and of PIK3CA hotspot mutation sites of ten breast and twenty salivary gland microdissected AcCCs revealed eight TP53 (80%) and one PIK3CA (10%) somatic mutations in breast AcCCs. No somatic mutations affecting these genes were found in the twenty salivary gland AcCCs analyzed. Conclusions Our findings demonstrate that breast AcCCs display TP53 and PIK3CA mutations at frequencies similar to those of common types of TNBCs, whereas these genes appear not to be altered in salivary gland AcCCs, suggesting that despite their similar histologic appearances, AcCCs of the breast and salivary glands likely constitute unrelated diseases.
    Histopathology 02/2015; · 3.30 Impact Factor
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    ABSTRACT: BLM has key roles in homologous recombination repair, telomere maintenance and DNA replication. Germ-line mutations in the BLM gene causes Bloom’s syndrome, a rare disorder characterised by premature aging and predisposition to multiple cancers including breast cancer. The clinicopathological significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n=1950) and validated in an external dataset of 2413 tumours. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1650 breast tumours. BLM mRNA overexpression was significantly associated with high histological grade, larger tumour size, ER negative, PgR negative and triple negative phenotypes (ps<0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes including PAM50.Her2 (p<0.0001), PAM50.Basal (p<0.0001) and PAM50.LumB (p<0.0001) and Genufu subtype (ER+/Her2-/High proliferation) (p<0.0001). PAM50.LumA tumours and Genufu subtype (ER+/Her2-/low proliferation) were more likely to express low levels of BLM mRNA (ps<0.0001). Integrative molecular clusters (intClust) intClust.1 (p<0.0001), intClust.5 (p<0.0001), intClust.9 (p<0.0001) and intClust.10 (p<0.0001) were also more likely in tumours with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer specific survival (BCSS) (ps<0.000001). At the protein level, altered sub-cellular localisation with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS (p=0.03). This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer.
    Molecular Cancer Therapeutics 02/2015; 2015 Feb 11. pii: molcanther.0939.2014. · 6.11 Impact Factor
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    ABSTRACT: BLM has key roles in homologous recombination repair, telomere maintenance and DNA replication. Germ-line mutations in the BLM gene causes Bloom’s syndrome, a rare disorder characterised by premature aging and predisposition to multiple cancers including breast cancer. The clinicopathological significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n=1950) and validated in an external dataset of 2413 tumours. BLM protein level was evaluated in the Nottingham Tenovus series comprising 1650 breast tumours. BLM mRNA overexpression was significantly associated with high histological grade, larger tumour size, ER negative, PgR negative and triple negative phenotypes (ps<0.0001). BLM mRNA overexpression was also linked to aggressive molecular phenotypes including PAM50.Her2 (p<0.0001), PAM50.Basal (p<0.0001) and PAM50.LumB (p<0.0001) and Genufu subtype (ER+/Her2-/High proliferation) (p<0.0001). PAM50.LumA tumours and Genufu subtype (ER+/Her2-/low proliferation) were more likely to express low levels of BLM mRNA (ps<0.0001). Integrative molecular clusters (intClust) intClust.1 (p<0.0001), intClust.5 (p<0.0001), intClust.9 (p<0.0001) and intClust.10 (p<0.0001) were also more likely in tumours with high BLM mRNA expression. BLM mRNA overexpression was associated with poor breast cancer specific survival (BCSS) (ps<0.000001). At the protein level, altered sub-cellular localisation with high cytoplasmic BLM and low nuclear BLM was linked to aggressive phenotypes. In multivariate analysis, BLM mRNA and BLM protein levels independently influenced BCSS (p=0.03). This is the first and the largest study to provide evidence that BLM is a promising biomarker in breast cancer. Most Senior and Corresponding Author: Dr Srinivasan Madhusudan
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    ABSTRACT: AimsAcinic cell carcinomas (AcCC) of the breast have been reported to constitute the breast counterpart of salivary gland AcCCs, based on the similarities of their histologic and immunohistochemical features. Breast AcCC is a vanishingly rare form of triple-negative breast cancer (TNBC). Recent studies have demonstrated that in TNBCs, the two driver genes most frequently mutated are TP53 (82%) and PIK3CA (10%). We sought to define whether breast AcCCs would harbor TP53 and PIK3CA somatic mutations, and if so, whether these would be present in salivary gland AcCCs.Methods and ResultsSanger sequencing of the entire coding region of TP53 and of PIK3CA hotspot mutation sites of ten breast and twenty salivary gland microdissected AcCCs revealed eight TP53 (80%) and one PIK3CA (10%) somatic mutations in breast AcCCs. No somatic mutations affecting these genes were found in the twenty salivary gland AcCCs analyzed.Conclusions Our findings demonstrate that breast AcCCs display TP53 and PIK3CA mutations at frequencies similar to those of common types of TNBCs, whereas these genes appear not to be altered in salivary gland AcCCs, suggesting that despite their similar histologic appearances, AcCCs of the breast and salivary glands likely constitute unrelated diseases.This article is protected by copyright. All rights reserved.
    Histopathology 02/2015; DOI:10.1111/his.12673 · 3.30 Impact Factor
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    ABSTRACT: Neoadjuvant chemotherapy (NACT) is increasingly used in the treatment of invasive breast cancer and presents challenges for the pathologist in the handling and interpretation of tissues. Potential issues include pathological identification and localisation of the residual tumour site; how best to assess pathological response (given the diversity of scoring systems described); the timing and assessment of axillary node biopsy; and the value of retesting any residual tumour for dissonance between core biopsy and post-treatment residual cancer cells for biomarker expression such as oestrogen and progesterone receptors, and HER2. The role of the pathologist is critical in modern NACT approaches to breast cancer and is likely to remain challenging as novel agents and newer biomarkers become available. In this manuscript we review these issues and describe some practical approaches to handling and reporting these samples in the routine histopathology laboratory. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Histopathology 01/2015; DOI:10.1111/his.12649 · 3.30 Impact Factor
  • Andrew H S Lee, Emad A Rakha, Ian O Ellis
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    ABSTRACT: The calpains are intracellular cysteine proteases that function in a variety of important cellular functions, including signalling, motility, apoptosis and survival. In breast cancer high calpain-1 and calpain-2 expression has been associated with adverse clinical outcome. Calpain-9 was thought to be exclusively expressed in the digestive tract; however recent studies have shown that this protein is also expressed in breast tissue. We investigated the expression of calpain-9 in a large cohort of early stage breast cancer patients (n = 783) using immunohistochemistry on a tissue microarray. Patients had long-term follow-up information available for analysis. Low expression of calpain-9 was associated with patients over 40 years of age (P = 0.025), smaller tumour size (P = 0.001), lower tumour stage (P = 0.009), a more favourable Nottingham Prognostic Index value (P = 0.002) and positive oestrogen receptor status (P = 0.014). Calpain-9 expression was not associated with survival in the total patient cohort, however low calpain-9 expression was associated with adverse survival in patients who received endocrine therapy (P = 0.033), which remained significant in multivariate Cox regression analysis accounting for potential confounding factors (hazard ratio (HR) = 0.56, 95% confidence interval (95% CI) = 0.36-0.89, P = 0.013). Low calpain-9 expression was also associated with adverse survival in patients with an intermediate Nottingham Prognostic Index value (P = 0.009), and remained so in multivariate analysis (HR = 0.54, 95% CI = 0.36-0.82, P = 0.003). This study suggests that calpain-9 may play a role in breast cancer and that low expression is associated with poorer patient clinical outcome following endocrine therapy. Validation studies are warranted as determining expression of calpain-9 may provide important prognostic information.
    BMC Cancer 12/2014; 14(1):995. DOI:10.1186/1471-2407-14-995 · 3.32 Impact Factor
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    ABSTRACT: Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well-characterised cohort of clinically annotated stage I-III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASγ and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASγ (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple-negative subgroup.
    Breast Cancer Research and Treatment 12/2014; 2014 Dec 21. [Epub ahead of print](2). DOI:10.1007/s10549-014-3230-1 · 4.20 Impact Factor

Publication Stats

5k Citations
1,042.83 Total Impact Points

Institutions

  • 2004–2015
    • University of Nottingham
      • • School of Molecular Medical Sciences
      • • Division of Molecular and Cellular Science
      Nottigham, England, United Kingdom
  • 2014
    • University of British Columbia - Vancouver
      • Department of Pathology and Laboratory Medicine
      Vancouver, British Columbia, Canada
  • 2005–2014
    • Nottingham University Hospitals NHS Trust
      • • Division of Histopathology
      • • Department of Cellular Pathology
      Nottigham, England, United Kingdom
    • The Queen's Medical Center
      Honolulu, Hawaii, United States
  • 2010
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 2008
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2007
    • Cardiff University
      Cardiff, Wales, United Kingdom
    • Nottingham Trent University
      Nottigham, England, United Kingdom
  • 2006
    • University Hospitals Of Leicester NHS Trust
      Leiscester, England, United Kingdom