Sunil R Lakhani

Royal Brisbane Hospital, Brisbane, Queensland, Australia

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Publications (121)833.46 Total impact

  • Sunil R Lakhani
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    ABSTRACT: The 4 edition of the WHO classification of Tumours of the Breast was published in 2012, as a separate volume from the gynae book. The editors and the international panel of breast pathologists have attempted to produce a consensus document that will help to standardize classification worldwide. In addition to microscopic criteria that define tumour types, there is incorporation of relevant updated molecular information.Many of the diagnostic problems in clinical practice reside in the B3 category, which comprises a heterogeneous group of proliferations that include atypical ductal hyperplasia (ADH), lobular neoplasia (ALH/LCIS), columnar cell lesions (CCL) and flat epithelial atypia (FEA), radial scar (RS/CSL), phyllodes tumours, papillary lesions, mucinous lesions and spindle cell proliferations. In clinical practice, the rate of B3-biopsies ranges from 3-10%.In this lecture, I will cover some of the diagnostic issues that have been discussed since the publication of the 4 edition. They centre on this group of lesions which form a significant component of consult practice throughput the world, suggesting that the diagnostic criteria and classification systems are still far from robust.
    Pathology 10/2014; 46 Suppl 2:S1. · 2.66 Impact Factor
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    ABSTRACT: Breast cancer is a complex, multifaceted disease encompassing a great variety of entities that show considerable variation in clinical, morphological and molecular attributes. Traditional classifications including histological assessment and clinical staging are used to guide patient management. In recent years, there has been exponential progress in molecular analysis with profound implications for our understanding of breast cancer biology and, hence, classification. There are now genome-based frameworks for the molecular categorisation of breast cancer including the development of prognostic and predictive signatures that potentially allow individualisation of treatment. Here we review the current state of the molecular classifications of in situ and invasive breast cancer including special subtypes. Future perspectives are also provided.
    Virchows Archiv : an international journal of pathology. 05/2014;
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    ABSTRACT: In this review, we highlight adaptations in the WHO 2012 classification of papillary and neuroendocrine breast lesions as compared to the previous 2003 version. Consensus criteria for distinguishing atypical ductal hyperplasia from ductal carcinoma in situ within an intraductal papilloma are proposed. Absence of myoepithelial cells around the wall of an encapsulated papillary carcinoma, while raising consideration of an indolent tumour with minimal invasion, is currently regarded as in situ disease for staging purposes. The majority of solid papillary carcinomas are classified as in situ tumours, but lesions with irregular tumour islands within desmoplastic stroma may be considered invasive. Diagnosis of solid papillary carcinoma without further qualification as either in situ or invasive disease is discouraged. When invasive papillary carcinoma is seen in the breast, metastatic papillary carcinoma from other organ sites needs to be excluded. WHO 2012 classifies neuroendocrine breast tumours into well differentiated neuroendocrine tumour, small cell carcinoma, and invasive breast carcinoma with neuroendocrine differentiation. There is currently no clinical impact of identifying neuroendocrine differentiation in conventional invasive breast carcinomas apart from acknowledging its frequent occurrence in subtypes such as the hypercellular variant of mucinous carcinoma and solid papillary carcinoma. This article is protected by copyright. All rights reserved.
    Histopathology 05/2014; · 2.86 Impact Factor
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    ABSTRACT: In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months.
    Oncotarget 04/2014; · 6.64 Impact Factor
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    ABSTRACT: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5 0 truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
    04/2014;
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    ABSTRACT: Our understanding of breast cancer heterogeneity at the protein level is limited despite proteins being the ultimate effectors of cellular functions. We investigated the heterogeneity of breast cancer (41 primary tumors and 15 breast cancer cell lines) at the protein and phosphoprotein levels to identify activated oncogenic pathways and developing targeted therapeutic strategies. Heterogeneity was observed not only across histological subtypes, but also within subtypes. Tumors of the Triple negative breast cancer (TNBC) subtype distributed across four different clusters where one cluster (cluster ii) showed high deregulation of many proteins and phosphoproteins. The majority of TNBC cell lines, particularly mesenchymal lines, resembled the cluster ii TNBC tumors. Indeed, TNBC cell lines were more sensitive than non-TNBC cell lines when treated with targeted inhibitors selected based on upregulated pathways in cluster ii. In line with the enrichment of the upregulated pathways with onco-clients of Hsp90, we found synergy in combining Hsp90 inhibitors with several kinase inhibitors, particularly Erk5 inhibitors. The combination of Erk5 and Hsp90 inhibitors was effective in vitro and in vivo against TNBC leading to upregulation of pro-apoptotic effectors. Our studies contribute to proteomic profiling and improve our understanding of TNBC heterogeneity to provide therapeutic opportunities for this disease.
    Oncotarget 03/2014; · 6.64 Impact Factor
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    ABSTRACT: Invasive lobular cancer (ILC) is an important contributor to false negative mammography. This study aims to assess the value of digital mammography and to identify imaging features that could assist the radiologist to suggest the diagnosis of ILC prior to biopsy. Three hundred sixty-one cases of pure ILC diagnosed at the Wesley Breast Clinic during the period 1995-2010 were reviewed by one of the authors (AP). Radiological features were categorized, and clinical features and needle sampling results were recorded. Mammography was negative in 29.9% of ILCs. The commonest positive finding was a localized spiculated mass (41.8%). Thirty-four point nine per cent of lesions were visible in only one view, usually cranio-caudal. Calcification was not a feature of ILC. The use of digital mammography in 30% of cases did not decrease the false negative rate for ILC. Breast ultrasound (BUS) showed an abnormality in 97.8%, most commonly a localized irregular hypoechoic mass with shadowing. Digital mammography does not reduce false negative mammography in ILC. The poor visibility of ILCs may be partly related to their low density (mass/unit volume). ILCs may sometimes be poor attenuators of X-rays but excellent attenuators of ultrasound, causing marked acoustic shadowing. Bilateral whole BUS has a very low false negative rate in experienced hands and is mandatory in symptomatic women. The combination of poor visibility on mammography with high visibility on ultrasound, as well as certain characteristic ultrasound appearances of ILC, may enable the radiologist to suggest ILC as a diagnostic possibility, prior to biopsy.
    Journal of Medical Imaging and Radiation Oncology 02/2014; 58(1):1-10. · 0.98 Impact Factor
  • Mark Bettington, Sunil R Lakhani, Owen A Ung
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    ABSTRACT: Intra-operative assessment of sentinel lymph nodes in breast cancer offers the opportunity to prevent two-stage surgical procedures. At our institution we employ touch imprint cytology (TIC), which lacks sensitivity. In this study we compare the one-step nucleic acid amplification (OSNA) assay to TIC. Imprints were taken from 63 lymph nodes from 35 patients. The lymph nodes were sectioned at 2-mm intervals and alternate slices submitted for either histology or OSNA assay, with histology as the reference standard. Seven patients were histologically positive. Nine and five patients were positive by OSNA and TIC, respectively. Sensitivity, specificity, positive and negative predictive value for the OSNA assay were 85.7%, 85.7%, 63.6% and 96.6% and for TIC were 70.0%, 96.6%, 87.5% and 90.3%. In this study OSNA had a higher sensitivity than TIC. Fewer patients assessed by the OSNA assay would have required a two-stage procedure. The OSNA assay appears to be a highly cost-effective method for providing rapid and reliable intra-operative assessment of sentinel lymph nodes.
    ANZ Journal of Surgery 01/2014; · 1.50 Impact Factor
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    ABSTRACT: Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.
    PLoS ONE 01/2014; 9(1):e86836. · 3.53 Impact Factor
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    ABSTRACT: Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain poorly understood. In this study, we identify a novel role for miR-139-5p in the inhibition of breast cancer progression. We highlight its clinical relevance by reviewing miR-139-5p expression across a wide variety of breast cancer subtypes using in-house generated and online data sets to show that it is most frequently lost in invasive tumors. A biotin pull-down approach was then used to identify the mRNA targets of miR-139-5p in the breast cancer cell line MCF7. Functional enrichment analysis of the pulled-down targets showed significant enrichment of genes in pathways previously implicated in breast cancer metastasis (P < 0.05). Further bioinformatic analysis revealed a predicted disruption to the TGFβ, Wnt, Rho, and MAPK/PI3K signaling cascades, implying a potential role for miR-139-5p in regulating the ability of cells to invade and migrate. To corroborate this finding, using the MDA-MB-231 breast cancer cell line, we show that overexpression of miR-139-5p results in suppression of these cellular phenotypes. Furthermore, we validate the interaction between miR-139-5p and predicted targets involved in these pathways. Collectively, these results suggest a significant functional role for miR-139-5p in breast cancer cell motility and invasion and its potential to be used as a prognostic marker for the aggressive forms of breast cancer.
    RNA 10/2013; · 5.09 Impact Factor
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    ABSTRACT: There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment, and pathology aspects of all cases and additionally, pathology features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c-Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases. Genomes of the primary tumour and multiple metastases were analyzed by array-based comparative genomic hybridization for six cases. 945 metastatic deposits were identified with a median of four per patient. The most common organs involved were lung/pleura (80%), bone (74%), liver (71%), and non-axillary lymph nodes (55%). Major findings included: i) patients with CNS metastases were more likely to have bone metastases (p<0·013); ii) younger age was associated with metastasis to the liver (≤49 years; p<0·001) and to gynaecological organs (≤49 years; p=0·001); iii) surgical excision of the primary tumour was associated with metastasis to the liver (p=0·002) and iv) ER and PgR showed down-regulation during progression in a non-random manner, particularly in lung/pleura (ER: p<0·001), liver, and bone metastases. Genomic analysis revealed DNA copy number variation between the primary tumour and metastases (e.g. amplification of 2q11.2-q12.1 and 10q22.2-q22.3) but little variation between metastases from the same patient. In summary, the association of CNS and bone metastases, liver and gynaecological metastases in young women and the risk of liver metastases following surgery have important implications for management of patients with breast cancer. Clonal heterogeneity of the primary tumour is important in developing metastatic propensity and the change in tumour phenotype during progression/colonization highlights the importance of sampling metastatic disease for optimal treatment strategies.
    The Journal of Pathology 10/2013; · 7.59 Impact Factor
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    ABSTRACT: The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.Oncogene advance online publication, 23 September 2013; doi:10.1038/onc.2013.368.
    Oncogene 09/2013; · 8.56 Impact Factor
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    ABSTRACT: All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
    Nature 08/2013; 500(7463):415-421. · 38.60 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
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    ABSTRACT: Pathology archives contain vast resources of clinical material in the form of formalin-fixed paraffin-embedded (FFPE) tissue samples. Owing to the methods of tissue fixation and storage, the integrity of DNA and RNA available from FFPE tissue is compromized, which means obtaining informative data regarding epigenetic, genomic, and expression alterations can be challenging. Here, we have investigated the utility of repairing damaged DNA derived from FFPE tumors prior to single-nucleotide polymorphism (SNP) arrays for whole-genome DNA copy number analysis. DNA was extracted from FFPE samples spanning five decades, involving tumor material obtained from surgical specimens and postmortems. Various aspects of the protocol were assessed, including the method of DNA extraction, the role of Quality Control quantitative PCR (qPCR) in predicting sample success, and the effect of DNA restoration on assay performance, data quality, and the prediction of copy number aberrations (CNAs). DNA that had undergone the repair process yielded higher SNP call rates, reduced log R ratio variance, and improved calling of CNAs compared with matched FFPE DNA not subjected to repair. Reproducible mapping of genomic break points and detection of focal CNAs representing high-level gains and homozygous deletions (HD) were possible, even on autopsy material obtained in 1974. For example, DNA amplifications at the ERBB2 and EGFR gene loci and a HD mapping to 13q14.2 were validated using immunohistochemistry, in situ hybridization, and qPCR. The power of SNP arrays lies in the detection of allele-specific aberrations; however, this aspect of the analysis remains challenging, particularly in the distinction between loss of heterozygosity (LOH) and copy neutral LOH. In summary, attempting to repair DNA that is damaged during fixation and storage may be a useful pretreatment step for genomic studies of large archival FFPE cohorts with long-term follow-up or for understanding rare cancer types, where fresh frozen material is scarce.Laboratory Investigation advance online publication, 8 April 2013; doi:10.1038/labinvest.2013.54.
    Laboratory Investigation 04/2013; · 3.96 Impact Factor
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    ABSTRACT: Triple-negative breast cancer (TNBC) is associated with poor survival. Chemotherapy is the only standard treatment for TNBC. The prevalence of BRCA1 inactivation in TNBC has rationalized clinical trials of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Similarly, the overexpression of epidermal growth factor receptor (EGFR) rationalized anti-EGFR therapies in this disease. However, clinical trials using these 2 strategies have not reached their promise. In this study, we used EGFR as a target for radioimmunotherapy and hypothesized that EGFR-directed radioimmunotherapy can deliver a continuous lethal radiation dose to residual tumors that are radiosensitized by PARP inhibitors and chemotherapy. METHODS: We analyzed EGFR messenger RNA in published gene expression array studies and investigated EGFR protein expression by immunohistochemistry in a cohort of breast cancer patients to confirm EGFR as a target in TNBC. Preclinically, using orthotopic and metastatic xenograft models of EGFR-positive TNBC, we investigated the effect of the novel combination of (177)Lu-labeled anti-EGFR monoclonal antibody, chemotherapy, and PARP inhibitors on cell death and the survival of breast cancer stem cells. RESULTS: In this first preclinical study of anti-EGFR radioimmunotherapy in breast cancer, we found that anti-EGFR radioimmunotherapy is safe and that TNBC orthotopic tumors and established metastases were eradicated in mice treated with anti-EGFR radioimmunotherapy combined with chemotherapy and PARP inhibitors. We showed that the superior response to this triple-agent combination therapy was associated with apoptosis and eradication of putative breast cancer stem cells. CONCLUSION: Our data support further preclinical investigations toward the development of combination therapies using systemic anti-EGFR radioimmunotherapy for the treatment of recurrent and metastatic TNBC.
    Journal of Nuclear Medicine 04/2013; · 5.77 Impact Factor
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    ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
    Nature Genetics 03/2013; 45(4):371-384. · 35.21 Impact Factor
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    ABSTRACT: Mammosphere and breast tumoursphere culture have gained popularity as in vitro assays for propagating and analysing normal and cancer stem cells. Whether the spheres derived from different sources or parent cultures themselves are indeed single entities enriched in stem/progenitor cells compared to other culture formats has not been fully determined. We surveyed sphere-forming capacity across 26 breast cell lines, immunophenotyped spheres from six luminal- and basal-like lines by immunohistochemistry and flow cytometry and compared clonogenicity between sphere, adherent and matrigel culture formats using in vitro functional assays. Analyses revealed morphological and molecular intra- and inter-sphere heterogeneity, consistent with adherent parental cell line phenotypes. Flow cytometry showed sphere culture does not universally enrich for markers previously associated with stem cell phenotypes, although we found some cell-line specific changes between sphere and adherent formats. Sphere-forming efficiency was significantly lower than adherent or matrigel clonogenicity and constant over serial passage. Surprisingly, self-renewal capacity of sphere-derived cells was similar/lower than other culture formats. We observed significant correlation between long-term-proliferating-cell symmetric division rates in sphere and adherent cultures, suggesting functional overlap between the compartments sustaining them. Experiments with normal primary human mammary epithelia, including sorted luminal (MUC1(+)) and basal/myoepithelial (CD10(+)) cells revealed distinct luminal-like, basal-like and mesenchymal entities amongst primary mammospheres. Morphological and colony-forming-cell assay data suggested mammosphere culture may enrich for a luminal progenitor phenotype, or induce reversion/relaxation of the basal/mesenchymal in vitro selection occurring with adherent culture. Overall, cell line tumourspheres and primary mammospheres are not homogenous entities enriched for stem cells, suggesting a more cautious approach to interpreting data from these assays and careful consideration of its limitations. Sphere culture may represent an alternative 3-dimensional culture system which rather than universally 'enriching' for stem cells, has utility as one of a suite of functional assays that provide a read-out of progenitor activity.
    PLoS ONE 01/2013; 8(6):e64388. · 3.53 Impact Factor
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    ABSTRACT: MicroRNAs are noncoding regulators of gene expression, which act by repressing protein translation and/or degrading mRNA. Many have been shown to drive tumorigenesis in cancer, but functional studies to understand their mode of action are typically limited to single-target genes. In this study, we use synthetic biotinylated miRNA to pull down endogenous targets of miR-182-5p. We identified more than 1000 genes as potential targets of miR-182-5p, most of which have a known function in pathways underlying tumor biology. Specifically, functional enrichment analysis identified components of both the DNA damage response pathway and cell cycle to be highly represented in this target cohort. Experimental validation confirmed that miR-182-5p-mediated disruption of the homologous recombination (HR) pathway is a consequence of its ability to target multiple components in that pathway. Although there is a strong enrichment for the cell cycle ontology, we do not see primary proliferative defects as a consequence of miR-182-5p overexpression. We highlight targets that could be responsible for miR-182-5p-mediated disruption of other biological processes attributed in the literature so far. Finally, we show that miR-182-5p is highly expressed in a panel of human breast cancer samples, highlighting its role as a potential oncomir in breast cancer.
    RNA 12/2012; · 5.09 Impact Factor
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    ABSTRACT: PURPOSE: More than 20 million archival tissue samples are stored annually in the United States as formalin-fixed, paraffin-embedded (FFPE) blocks, but RNA degradation during fixation and storage has prevented their use for transcriptional profiling. New and highly sensitive assays for whole-transcriptome microarray analysis of FFPE tissues are now available, but resulting data include noise and variability for which previous expression array methods are inadequate.EXPERIMENTAL DESIGN: We present the two largest whole-genome expression studies from FFPE tissues to date, comprising 1,003 colorectal cancer (CRC) and 168 breast cancer samples, combined with a meta-analysis of 14 new and published FFPE microarray datasets. We develop and validate quality control (QC) methods through technical replication, independent samples, comparison to results from fresh-frozen tissue, and recovery of expected associations between gene expression and protein abundance.RESULTS: Archival tissues from large, multicenter studies showed a much wider range of transcriptional data quality relative to smaller or frozen tissue studies and required stringent QC for subsequent analysis. We developed novel methods for such QC of archival tissue expression profiles based on sample dynamic range and per-study median profile. This enabled validated identification of gene signatures of microsatellite instability and additional features of CRC, and improved recovery of associations between gene expression and protein abundance of MLH1, FASN, CDX2, MGMT, and SIRT1 in CRC tumors.CONCLUSIONS: These methods for large-scale QC of FFPE expression profiles enable study of the cancer transcriptome in relation to extensive clinicopathological information, tumor molecular biomarkers, and long-term lifestyle and outcome data. Clin Cancer Res; 18(22); 1-11. ©2012 AACR.
    Clinical Cancer Research 11/2012; · 7.84 Impact Factor

Publication Stats

6k Citations
833.46 Total Impact Points

Institutions

  • 2010–2014
    • Royal Brisbane Hospital
      Brisbane, Queensland, Australia
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2005–2014
    • University of Queensland
      • • UQ Centre for Clinical Research
      • • Department of Molecular and Cellular Pathology
      Brisbane, Queensland, Australia
  • 2012–2013
    • Wellcome Trust Sanger Institute
      • Cancer Genome Project
      Cambridge, England, United Kingdom
  • 2006–2013
    • Queensland Institute of Medical Research
      • Signal Transduction Laboratory
      Brisbane, Queensland, Australia
  • 2011
    • University of Utah
      • Department of Dermatology
      Salt Lake City, UT, United States
  • 2002–2007
    • Institute of Cancer Research
      • Division of Breast Cancer Research
      Londinium, England, United Kingdom
  • 2003–2006
    • Breakthrough Breast Cancer
      Londinium, England, United Kingdom