Emad A Rakha

University of Nottingham, Nottigham, England, United Kingdom

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Publications (212)1095.47 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin α-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC. METHODS: A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry. RESULTS: KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, γH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P<0.0001), but this effect was not independent of other prognostic variables. CONCLUSIONS: This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function.
    British Journal of Cancer 05/2015; 2015 May 19. doi: 10.1038/bjc.2015.165.. DOI:10.1038/bjc.2015.165. · 4.82 Impact Factor
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    ABSTRACT: Stratification of oestrogen receptor (ER) negative and triple negative breast cancers (TNBCs) is urgently needed. In the current study, a cohort of 880 ER- (including 635 TNBCs) was immuno-profiled for a panel of DNA repair proteins including: Pol β, FEN1, APE1, XRCC1, SMUG1, PARP1, BRCA1, ATR, ATM, DNA-PKcs, Chk1, Chk2, p53, and TOPO2. Multivariate Cox proportional hazards models (with backward stepwise exclusion of these factors, using a criterion of p <0.05 for retention of factors in the model) were used to identify factors that were independently associated with clinical outcomes. XRCC1 (p=0.002), pol β (p=0.032) FEN1 (p=0.001) and BRCA1 (p= 0.040) levels were independently associated with poor BCSS. Subsequently, DNA repair index prognostic (DRPI) scores for breast cancer specific survival (BCSS) were calculated and two prognostic groups (DRPI-PGs) were identified. Patients in prognostic group 2 (DRPI-PG2) have higher risk of death (p<0.001). Furthermore, in DRPI-PG2 patients, exposure to anthracycline reduced the risk of death [(HR (95% CI) = 0.79 (0.64-0.98), p=0.032) by 21-26%. In addition, DRPI-PG2 patients have adverse clinicopathological features including higher grade, lympho-vascular invasion, Her-2 positive phenotype, compared to those in DRPI-PG1 (p<0.01). Receiver operating characteristic (ROC) curves indicated that the DRPI outperformed the currently used prognostic factors and adding DRPI to lymph node stage significantly improved their performance as a predictor for BCSS [p <0.00001, area under curve (AUC) =0.70]. BER strongly influences pathogenesis of ER- and TNBCs. The DRPI accurately predicts BCSS and can also serve as a valuable prognostic and predictive tool for TNBCs.
    Oncotarget 05/2015; In Press. · 6.63 Impact Factor
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    ABSTRACT: Accurate distant metastasis (DM) prediction is critical for risk stratification and effective treatment decisions in breast cancer (BC). Many prognostic markers/models based on tissue marker studies are continually emerging using conventional statistical approaches analysing complex/dimensional data association with DM/poor prognosis. However, few of them have fulfilled satisfactory evidences for clinical application. This study aimed at building DM risk assessment algorithm for BC patients. A well-characterised series of early invasive primary operable BC (n = 1902), with immunohistochemical expression of a panel of biomarkers (n = 31) formed the material of this study. Decision tree algorithm was computed using WEKA software, utilising quantitative biomarkers' expression and the absence/presence of distant metastases. Fifteen biomarkers were significantly associated with DM, with six temporal subgroups characterised based on time to development of DM ranging from <1 to >15 years of follow-up. Of these 15 biomarkers, 10 had a significant expression pattern where Ki67LI, HER2, p53, N-cadherin, P-cadherin, PIK3CA and TOMM34 showed significantly higher expressions with earlier development of DM. In contrast, higher expressions of ER, PR and BCL2 were associated with delayed occurrence of DM. DM prediction algorithm was built utilising cases informative for the 15 significant markers. Four risk groups of patients were characterised. Three markers p53, HER2 and BCL2 predicted the probability of DM, based on software-generated cut-offs, with a precision rate of 81.1 % for positive predictive value and 77.3 %, for the negative predictive value. This algorithm reiterates the reported prognostic values of these three markers and underscores their central biological role in BC progression. Further independent validation of this pruned panel of biomarkers is therefore warranted.
    Breast Cancer Research and Treatment 05/2015; 151(2). DOI:10.1007/s10549-015-3406-3 · 4.20 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P5-09-01-P5-09-01. DOI:10.1158/1538-7445.SABCS14-P5-09-01 · 9.28 Impact Factor
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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; 112(9). 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; 150(3). 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; 150(1). 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
    Molecular Cancer Therapeutics 02/2015; DOI:10.1158/1535-7163.MCT-14-0939 · 6.11 Impact Factor
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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

Publication Stats

5k Citations
1,095.47 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