Emad A Rakha

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada

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Publications (169)715.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BRCA1, a key factor in homologous recombination repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol ß protein expression in two cohorts (n=1602 sporadic and n=50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n=1952 and n=249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol ß at mRNA and protein levels (p<0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol ß expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol ß expressing BRCA1 negative tumours (ps<0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol ß. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol ß expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy.
    Molecular Oncology 08/2014; In Press. · 6.70 Impact Factor
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    ABSTRACT: The extracellular-regulated kinase (ERK) 1/2 is one of the members of the mitogen-activated protein kinases (MAPKs). MAPKs are transduction proteins that play a role in controlling diverse cellular functions including proliferation and survival. In breast cancer (BC), MAPKs are involved in oestrogen receptor (ER) and HER2 pathways. This study aims to assess the biological and clinical significance of ERK1/2 protein expression in BC. Immunohistochemistry was used to assess the expression of both total (ERK1/2) and phospholyated (p ERK1/2) ERK1/2 proteins in a large and well-characterised series of early stage BC (n = 1300) using tissue microarray technology. ERK1/2 expression was cytoplasmic, while p-ERK1/2 was observed in the nucleus (N-p-ERK1/2) and/or cytoplasm (C-p-ERK1/2). Both ERK1/2 and p-ERK1/2 were positiviely associated with markers of good prognosis including smaller size, lower grade, expression of hormone receptor and ER-related proteins and negatively associated with HER2, HER4, KI67 and p53. Outcome analysis showed an association between N-p-ERK1/2 and better outcome. In tamoxifen-treated cases, ERK1/2 expression was an independent prognostic marker of longer survival. ERK1/2 and p-ERK1/2 were associated with good prognosis. Importantly, positivity of ERK1/2 is independently associated with better outcome in tamoxifen-treated cases.
    Breast Cancer Research and Treatment 08/2014; · 4.47 Impact Factor
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    ABSTRACT: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end-joining pathway required for the repair of DNA double-strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. We evaluated clinicopathological significance of DNA-PKcs protein expression in 1,161 tumours and DNA-PKcs mRNA expression in 1,950 tumours. We correlated DNA-PKcs to markers of aggressive phenotypes, DNA repair, apoptosis, cell cycle regulation and survival. Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps < 0.05). The absence of BRCA1, low XRCC1, low SMUG1, low APE1 and low Polβ was also more likely in low DNA-PKcs expressing tumours (ps < 0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer-specific survival (BCSS) in univariate and multivariate analysis (ps < 0.01). At the mRNA level, similarly, low DNA-PKcs was associated with poor BCSS. In patients with ER-positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER-negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers.
    Breast Cancer Research and Treatment 06/2014; · 4.47 Impact Factor
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    ABSTRACT: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 06/2014;
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    ABSTRACT: Epithelial mesenchymal transition (EMT), as defined by loss of epithelial characteristics and gain of a mesenchymal phenotype, has been reported in vivo although the occurrence of events remains unclear. This study aims at exploration of EMT portraits of breast cancer (BC) with relevance to different molecular pathways, especially potential EMT triggers and BC molecular subtypes. Immunohistochemical (IHC) expression of markers/triggers of EMT was studied on a well-defined cohort of invasive non-lobular BC (n = 1,035), prepared as tissue microarrays. IHC panel of biomarkers included cadherins (cad; E-cad and N-cad), TGFβ1, PIK3CA, pAkt, and others. Reverse phase protein array (RPPA) was performed for quantitative analysis of proteins extracted from formalin fixed paraffin embedded tissues of a subset of cases from this cohort. Four combinatorial phenotypic groups representing cadherin switch were defined, including E-cad(+)/N-cad(-), E-cad(-)/N-cad(-), E-cad(+)/N-cad(+), and E-cad(-)/N-cad(+). Statistically significant association was noticed between these phenotypes and histological tumour grade, tumour type and size and NPI staging classes. The E-cad/N-cad switch occurred more frequently in the triple negative molecular class, both basal and non-basal, and in the HER2(+) subtype than in luminal BC. Significant outcome differences were observed between cadherin switch combinatorial groups regarding BCSS and DMFS (p < 0.001). Results of RPPA confirm those observed using IHC regarding differential expressions of EMT markers/triggers. EMT/cadherin switch programs in BC appear to occur in synergy with TGFβ1 and PIK3/Akt pathways activation. These data explain, at translational proteomic level, the molecular heterogeneity and in turn the varied clinical behaviour of BC molecular subtypes. RPPA is a promising high-throughput technique in monitoring subtle quantitative changes in protein expression in archival material.
    Breast Cancer Research and Treatment 04/2014; · 4.47 Impact Factor
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    ABSTRACT: The definition of Luminal-B subclass of breast cancer (BC) varies in literature. In this study, we have compared the proliferation status; assessed using KI67 labeling index (KI67-LI), and HER2-expression in estrogen receptor positive (ER+) BC to assess their impact on the biological and clinical characteristics of luminal-BC. 1547 (73.8 %) well-characterized clinically annotated stage I-III ER + BC were assessed for expression of KI67, HER2 (ASCO guidelines), and a large panel of relevant biomarkers (no = 37). 46.3 % of the cases show high KI67-LI (>13 %) and 8.4 % show HER2+ and both markers are positively associated with younger age, higher tumor grade and poorer outcome. High KI67-LI and HER2+ are associated with upregulation of ER-coactivators and proliferation-related markers and with downregulation of good prognostic markers. High KI67-LI is associated with larger size, advanced stage, and lymphovascular invasion (LVI) and with downregulation of luminal-enriched and DNA-damage repair markers. In contrast, HER2+ is associated with upregulation of ER-regulated proteins and E-cadherin. When analysis is restricted to high KI67-LI subgroup, HER2+ shows an association with upregulation of differentiation-associated proteins and E-cadherin. Conversely, within HER2+ class, high KI67-LI maintains its association with downregulation of differentiation-associated/luminal-enriched proteins. Outcome analyses indicate that both markers are independently associated with shorter survival but HER2+ is associated with a worse outcome. Although both are associated with high proliferation and poor prognosis within ER + BC, HER2+ is less frequent than high KI67-LI. Unlike KI67, HER2 seems to independently drive the aggressive behavior of ER+ tumors without downregulation of luminal proteins.
    Breast Cancer Research and Treatment 04/2014; · 4.47 Impact Factor
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    ABSTRACT: Human epidermal growth factor receptor 2 (HER2) plays an important role in breast cancer progression and provides predictive information for response to targeted therapy including trastuzumab although this is limited. Downstream pathways, such as PI3K/Akt, are associated with HER2/HER3 heterodimerization promoting survival and proliferation amongst cancer cells. Thus, patient outcome and trastuzumab therapy effectiveness might be further characterised by HER2/HER3 dimerisation and its signalling pathways. HER2/HER3 dimerisation status was assessed, using chromogenic in situ Proximity Ligation Assay, in two breast cancer series: early stage primary breast cancer, including 224 HER2+ patients that were not submitted to trastuzumab, and HER2+ breast cancer where patients were treated with adjuvant trastuzumab (n = 143). Levels of biomarkers including PI3K, pAKT, ER, PgR, HER3, BCL2, p53, PTEN and p21 were measured using immunohistochemistry. Levels of HER2/HER3 heterodimers were compared with biomarker expression and patient outcome. An association between high levels of HER2/HER3 dimerisation and absence of hormone receptors, ER and PgR, was observed. We further show for the first time the presence of HER2/HER3 heterodimers and the loss of p21 expression in HER2+ breast cancer predicts a significantly poorer outcome when submitted to adjuvant trastuzumab. Breast cancer patients that reveal high levels of HER2/HER3 dimerisation and loss of p21 are associated with poor survival prognosis in patients with HER2+ breast cancer treated with adjuvant trastuzumab. Further quantification analysis of HER dimer/ligand complexes and downstream signalling pathways will begin to unravel the complex associations with patient outcome and its relationship with sensitivity to targeted treatment.
    Breast Cancer Research and Treatment 04/2014; · 4.47 Impact Factor
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    ABSTRACT: Advances in breast cancer (BC) research have demonstrated differences between black and white women with regarding tumour behaviour, patient outcome and response to treatment which can be explained by underlying genetic changes. The tumour suppressor gene p53 has been speculated to be involved in tumour biology of triple negative and/or basal -like BC and more commonly observed in black than caucasian women. In this study, the protein expression of p53 was investigated in tissue samples from a series of 308 Nigerian women, prepared as a tissue microarray (TMA), using immunohistochemistry. Clinicopathological parameters, biomarkers of functional significance in BC and patient outcome of tumours expressing p53 in Nigerian women were correlated with UK grade matched series. A significantly large proportion of BC from Nigerian women showed high p53 expression compared with UK women (p<0.001). In those tumours showing positive p53 in the Nigerian series, a significant proportion were premenopausal, diagnosed before 50 years, larger in size, with evidence of metastasis into lymphatic vessels ( all p<0.001). In addition, p53 positive expression was also significantly correlated with negative expression of ER and PgR (p<0.001, p<0.03 respectively), BRCA1, MDM2 (all p<0.001), p21 (p=0.006) and E-cadherin (p=0.001) and positively associated with P-cadherin (p=0.001), triple negative phenotype, basal cytokeratin (CK) 5/6 expression (p<0.04) and basal phenotype compared with the UK series (p<0.001). Survival analyses showed Nigerian women with BC were significantly associated with poor BC specific survival (p<0.001, but no significant association with disease free interval was observed. In this study, protein expressions of p53 pathways are different between Nigerian and UK BC women and this may also contribute to differences in tumour biology. Therefore, targeting these p53 pathways for therapeutic usage might improve the poor outcome observed in Black Nigerian women.
    The Malaysian journal of pathology 04/2014; 36(1):3-17.
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    ABSTRACT: Background:Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. Global gene expression profiling studies have demonstrated that BC comprises distinct molecular classes with clinical relevance. In this study, we hypothesised that molecular features of BC are a key driver of tumour behaviour and when coupled with a novel and bespoke application of established clinicopathologic prognostic variables can predict both clinical outcome and relevant therapeutic options more accurately than existing methods.Methods:In the current study, a comprehensive panel of biomarkers with relevance to BC was applied to a large and well-characterised series of BC, using immunohistochemistry and different multivariate clustering techniques, to identify the key molecular classes. Subsequently, each class was further stratified using a set of well-defined prognostic clinicopathologic variables. These variables were combined in formulae to prognostically stratify different molecular classes, collectively known as the Nottingham Prognostic Index Plus (NPI+). The NPI+ was then used to predict outcome in the different molecular classes.Results:Seven core molecular classes were identified using a selective panel of 10 biomarkers. Incorporation of clinicopathologic variables in a second-stage analysis resulted in identification of distinct prognostic groups within each molecular class (NPI+). Outcome analysis showed that using the bespoke NPI formulae for each biological BC class provides improved patient outcome stratification superior to the traditional NPI.Conclusion:This study provides proof-of-principle evidence for the use of NPI+ in supporting improved individualised clinical decision making.British Journal of Cancer advance online publication: 11 March 2014. doi:10.1038/bjc.2014.120 www.bjcancer.com.
    British Journal of Cancer 03/2014; · 5.08 Impact Factor
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    ABSTRACT: Small Ubiquitin-like Modifier proteins (or SUMO) modify the function of protein substrates involved in various cellular processes including DNA damage response (DDR). It is becoming apparent that dysregulated SUMO contribute to carcinogenesis by affecting post-transcriptional modification of key proteins. It is hypothesised that SUMO contributes to the aggressive nature of breast cancer particularly those associated with features similar to breast carcinoma arising in patients with BRCA1 germline mutations. This study aims to assess the clinical and biological significance of three members of SUMO in a well-characterised annotated series of BC with emphasis on DDR. The study cohort comprised primary operable invasive BC including tumours from patients with known BRCA1 germline mutations. SUMO proteins PIAS1, PIAS4 and UBC9 were assessed using immunohistochemistry utilising tissue microarray technology. Additionally, their expression was assessed using reverse phase protein microarray utilising different cell lines. PIAS1 and UBC9 showed cytoplasmic and/or nuclear expression while PIAS4 was detected only in the nuclei. There was a correlation between subcellular localisation and expression of the nuclear transport protein KPNA2. Tumours showing positive nuclear/negative cytoplasmic expression of SUMO featured good prognostic characteristics including lower histologic grade and had a good outcome. Strong correlation with DDR-related proteins including BRCA1, Rad51, ATM, CHK1, DNA-PK and KU70/KU80 was observed. Correlation with ER and BRCA1 was confirmed using RPPA on cell lines. SUMO proteins seem to play important role in BC. Not only expression but also subcellular location is associated with BC phenotype.
    Breast Cancer Research and Treatment 03/2014; · 4.47 Impact Factor
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    ABSTRACT: HER2 plays an important role in breast cancer progression and provides predictive and prognostic information. HER2 receptor family members function through dimerisation, which can lead to impact on cell function, growth and differentiation; however, their value in breast cancer development remains to be defined. This study aims to examine the relationships of HER2 heterodimers to breast cancer characteristics in trastuzumab naïve and treated cases. HER2 protein (IHC), HER2 gene (chromogenic ISH) and HER2 heterodimerisation status [chromogenic in situ proximity ligation assay (PLA)] were assessed in two breast cancer series prepared in tissue microarray (TMA) format. A range of signals/cell for each HER2 heterodimer was detected (0-34.6 signals/cell). The vast majority of cases with HER2 heterodimers showed HER2 gene amplification and/or protein expression. There was an association between HER2 dimerisation with HER3 and HER4 and their protein expression level but no such association was found in with HER1 (EGFR). Of the HER2+ cases, 74, 66, and 58 % showed heterodimers with EGFR, HER3 and HER4, respectively. 51 % of HER2+ tumours expressed all three heterodimers whereas 23 % of the cases did not show expression of any of the three heterodimers. There was an inverse association between the presence and levels of HER2 heterodimers and hormone receptor expression in HER2+ tumours. Tumours exhibiting high levels of HER2 heterodimers demonstrated aggressive clinicopathological features and poor outcome. In the HER2+ cases, dimerisation with EGFR and HER3 but not with HER4 showed an association with aggressive features. There was no association between HER2 heterodimers with patient breast cancer-specific survival or recurrence in HER2+ breast cancer in those patients receiving trastuzumab or not. Our results demonstrate that HER2 dimerisation is a complex process that may underlie the biological heterogeneity of HER2 positive tumours and may identify patients suitable for a specific targeted therapy but does not predict patient outcome for those receiving trastuzumab. PLA proved to be a useful tool for detecting, visualising and quantifying the frequency of protein-protein interactions in archival formalin-fixed paraffin-embedded tissue samples.
    Breast Cancer Research and Treatment 02/2014; · 4.47 Impact Factor
  • European Journal of Surgical Oncology (EJSO). 01/2014; 40(5):607.
  • Emad A Rakha, Andrew H S Lee, Ian O Ellis
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    ABSTRACT: The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have issued a joint updated comprehensive guideline recommendations for HER2 testing in breast cancer. The current update not only provides guideline of the test performance parameters that aims to improve test accuracy, reproducibility and precision but also provides comprehensive recommendation on the post-analytical interpretation of the results and requires improved communication among health care providers. The update guideline is targeting testing laboratories and pathologists, oncologists, surgeons and indirectly other health care providers. Although the guidelines contribute to improved analytical validity and clinical utility of laboratory assays required for successful molecularly targeted therapy in the era of personalised medicine, implications for such recommendations have to be acknowledged. Certain recommendations particularly those related to repeating the test and pathological concordance have limited levels of supportive evidence than for existing key recommendations and the workload implications associated will be challenging to support in most healthcare systems. In this commentary we critically address the key updated recommendations and their impact on service provision and patients care. This article is protected by copyright. All rights reserved.
    Histopathology 12/2013; · 2.86 Impact Factor
  • Emad A Rakha, Ian O Ellis
    Nature Reviews Clinical Oncology 12/2013; · 15.03 Impact Factor
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    ABSTRACT: Indigenous black women with breast cancer (BC) show a high frequency of triple negative breast cancer (TNBC) comprising ER-, PR- and HER2- phenotypes and BRCA1 deficiency together with a high mortality rate, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours may be different to those of Western women. Protein inhibitor of activated signal transducer (PIAS) γ implicated in the BRCA1 deficiency and triple negative BC was investigated to establish the relationship among the small ubiquitin-like modifier marker, pathological features, biomarkers expression and clinical outcome in the black women. This study investigated the immunoprofiles of PIASγ in 231 Nigerian BC prepared as tissue microarrays and correlated their protein expression with clinical outcome, pathological responses and the expression of 14 other relevant biomarkers. PIASγ protein expression showed a significant correlation with higher histological grade, basal-like biomarkers expression (CK14, CK5/6 and EGFR), BRCA1 regulator (MTA1), p53, PI3KCA, basal-like phenotype and TNBC. Also, an inverse correlation with steroid hormones (ER and PgR), p27, MDM4, mucin 1 and BRCA1 was observed with PIASγ expression. Univariate and multivariate survival analyses showed PIASγ expression was a predictor of poor outcome independent of tumour histological grade and ER expression. PIASγ appears to be important in breast cancer behaviour arising from Nigerian women. PIASγ may therefore be useful for the screening of basal-like and TNBC. Also, development of novel therapies towards targeting PIASγ functional pathways may enhance the BC management among this ethnic nationality.
    Journal of clinical pathology 10/2013; · 2.43 Impact Factor
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    ABSTRACT: Basal-like (BL) breast cancer is an aggressive form of breast cancer with limited treatment options. Recent work has identified BL breast cancer as a biologically distinct form of triple-negative breast cancer, with a worse outlook. The receptor tyrosine kinase c-Met is a novel therapeutic target associated with reduced survival in breast cancer. Few studies have specifically addressed the association between c-Met and molecular subtype of breast cancer, yet this is a key consideration when selecting patients for clinical trials. The aim of this study is to evaluate c-Met expression in a large cohort of invasive breast cancers and in particular, its correlation with molecular subtype. Immunohistochemistry for c-Met was performed and evaluated on 1274 invasive breast cancers using tissue microarray technology. The c-Met scores were correlated with molecular subtype, survival, and other standard clinicopathological prognostic factors. Multivariate logistic regression showed c-Met was independently associated with BL status (odds ratio = 6.44, 95% confidence interval = 1.74-23.78, P = .005). There was a positive correlation between c-Met and Her2 (P = .005) and an inverse correlation with tumor size (P < .001). C-Met was an independent poor prognostic factor at Cox regression analysis in all subtypes (hazard ratio = 1.85, 95% confidence interval = 1.07-3.19, P = .027) and there was a trend toward reduced survival in BL tumors overexpressing c-Met, but this was not significant. C-Met is independently associated with BL breast cancer. In the future, patients with BL tumors should be included in clinical trials of anti-c-Met therapy. Cancer 2013;. © 2013 American Cancer Society.
    Cancer 10/2013; · 5.20 Impact Factor
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    ABSTRACT: The majority of breast cancers (BC) in Nigerian women are triple negative and show breast cancer-associated gene 1 (BRCA1) deficiency as well as the basal like phenotype, with a high mortality rate. In contrast to the well-defined predictive factors for the hormonal therapy, there is a paucity of information on the BRCA1 deficiency breast tumor biology, particularly among African women. BRCA1 Sumoylation (UBC9) has been speculated to be involved in the ER transcription activity, BRCA1 deficiency and triple negative BC. We therefore hypothesized that UBC9, a SUMOylation marker, may have contributed to the aggressive nature of BRCA1 tumor phenotype observed in Nigerian women. This study investigated the immunoprofiles of UBC9 in tissue microarray (TMA) of 199 Nigerian women and correlated their protein expression with clinical outcome, pathological responses and the expression of other biomarkers to demonstrate the functional significance in Nigerian women. The protein expression of UBC9, as compared with other biomarkers, showed an inverse correlation with steroid hormones (ER, progesterone (PgR)), BRCA1, p27, p21 and MDM4, and a positive correlation with triple negative, basal cytokeratins (CK14 and CK5/6), epidermal growth factor receptor (EGFR), basal-like breast cancer phenotype, p53, phosphoinositide-3-kinases (PI3KCA), placental cadherin, (P-cadherin) and BRCA1 regulators (metastasis tumor antigen-1 (MTA1). Survival analysis showed that those tumors positive for UBC9 expression had a significantly poorer breast cancer-specific survival (BCSS) as compared with those showing negative expression. UBC9 remained an independent predictor of outcome for BCSS. This study demonstrates that UBC9 appears to play an important role in the tumor biology of Nigerian women. Therefore, a novel UBC9 targeted therapy in black women with BC could enhance a better patient outcome.
    Pathology - Research and Practice 10/2013; · 1.21 Impact Factor
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    ABSTRACT: Background:Breast cancer is a heterogeneous disease characterised by complex molecular alterations underlying the varied behaviour and response to therapy. However, translation of cancer genetic profiling for use in routine clinical practice remains elusive or prohibitively expensive. As an alternative, immunohistochemical analysis applied to routinely processed tissue samples could be used to identify distinct biological classes of breast cancer.Methods:In this study, 1073 archival breast tumours previously assessed for 25 key breast cancer biomarkers using immunohistochemistry and classified using clustering algorithms were further refined using naïve Bayes classification performance. Criteria for class membership were defined using the expression of a reduced panel of 10 proteins able to identify key molecular classes. We examined the association between these breast cancer classes with clinicopathological factors and patient outcome.Results:We confirm patient classification similar to established genotypic biological classes of breast cancer in addition to novel sub-divisions of luminal and basal tumours. Correlations between classes and clinicopathological parameters were in line with expectations and showed highly significant association with patient outcome. Furthermore, our novel biological class stratification provides additional prognostic information to the Nottingham Prognostic Index.Conclusion:This study confirms that distinct molecular phenotypes of breast cancer can be identified using robust and routinely available techniques and both the luminal and basal breast cancer phenotypes are heterogeneous and contain distinct subgroups.British Journal of Cancer advance online publication, 5 September 2013; doi:10.1038/bjc.2013.528 www.bjcancer.com.
    British Journal of Cancer 09/2013; · 5.08 Impact Factor
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    ABSTRACT: The coactivator-associated arginine methyltransferase-1 (CARM1) is implicated in regulation of oestrogen receptor (ER) α-mediated gene pathways in response to ER activation. It plays an important role in breast cancer growth by regulating the E2F1 expression suggesting that CARM1 could be a target in the subclassification of oestrogen-dependent breast cancer. This study aims to investigate the clinical and biological importance of CARM1 protein expression in a large (1,130 patients), well-characterised and annotated series of invasive breast cancers using tissue microarrays and immunohistochemistry. In the whole series, increased CARM1 expression is correlated with features associated with aggressive behaviour such as young age, premenopausal status, large tumour size and high tumour grade. There is a positive correlation between CARM1 expression and biomarkers associated with non-luminal phenotype and poor prognosis such as HER2, basal cytokeratins, EGFR, p53 and the proliferation markers Ki67, TK1, CD71 and Cyclin E. Negative associations with the luminal-associated markers including steroid receptors and luminal cytokeratins are found. Similar associations are identified in the ER-positive/luminal subgroup (n = 767). Outcome analyses indicate that CARM1 expression is an independent predictor of shorter breast cancer-specific survival and disease-free interval in the whole series and in the ER-positive subgroup. CARM1 shows an oncogenic effect in breast cancer and its expression is associated with poor prognosis. CARM1 could be a potential marker of luminal class subclassification and for target therapy, particularly in the ER-positive luminal-like subgroup.
    Breast Cancer Research and Treatment 07/2013; · 4.47 Impact Factor
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    ABSTRACT: Lobular neoplasia (LN) is a term that encompasses both lobular carcinoma in situ and atypical lobular hyperplasia. These lesions have been shown to constitute both risk indicators and nonobligate precursors of invasive breast cancer, they are relatively uncommon, and are most often identified in specimens taken for other reasons. Their incidence has increased in the last 2 decades, and novel variants, including a pleomorphic type, have been described. Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions. The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex. This review provides an update on recent clinicopathologic and molecular data on LN and invasive lobular carcinoma and a discussion about the use and limitations of IHC with E-cadherin in diagnostic breast pathology.
    The American journal of surgical pathology 07/2013; 37(7):e1-e11. · 4.06 Impact Factor

Publication Stats

4k Citations
715.11 Total Impact Points


  • 2014
    • University of British Columbia - Vancouver
      • Department of Pathology and Laboratory Medicine
      Vancouver, British Columbia, Canada
  • 2004–2014
    • University of Nottingham
      • School of Molecular Medical Sciences
      Nottigham, England, United Kingdom
  • 2013
    • Olabisi Onabanjo University
      • Department of Morbid Anatomy and Histopathology
      Ago Are, Nigeria
  • 2005–2013
    • Nottingham University Hospitals NHS Trust
      • • Division of Histopathology
      • • Department of Cellular Pathology
      Nottigham, England, United Kingdom
    • National University of Singapore
      • Department of Pathology
      Singapore, Singapore
  • 2011
    • Erasmus MC
      • Department of Pathology
      Rotterdam, South Holland, Netherlands
  • 2010
    • Suez Canal University
      Al Ismā‘īlīyah, Al Ismā‘īlīyah, Egypt
    • Indiana University-Purdue University Indianapolis
      Indianapolis, Indiana, United States
    • Mansoura University
      • Department of Pathology
      Ṭalkha, Muhafazat ad Daqahliyah, Egypt
  • 2008
    • Nottinghamshire Healthcare NHS Trust
      Nottigham, England, United Kingdom
    • McGill University
      Montréal, Quebec, Canada
  • 2006
    • University Hospitals Of Leicester NHS Trust
      Leiscester, England, United Kingdom