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author:("Nair, vedhika")
1.  MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene 
The study of mammalian development has offered many insights into the molecular aetiology of cancer. We previously used analysis of mammary morphogenesis to discover a critical role for GATA-3 in mammary developmental and carcinogenesis. In recent years an important role for microRNAs (miRNAs) in a myriad of cellular processes in development and in oncogenesis has emerged.
microRNA profiling was conducted on stromal and epithelial cellular subsets microdissected from the pubertal mouse mammary gland. miR-184 was reactivated by transient or stable overexpression in breast cancer cell lines and examined using a series of in vitro (proliferation, tumour-sphere and protein synthesis) assays. Orthotopic xenografts of breast cancer cells were used to assess the effect of miR-184 on tumourigenesis as well as distant metastasis. Interactions between miR-184 and its putative targets were assessed by quantitative PCR, microarray, bioinformatics and 3′ untranslated region Luciferase reporter assay. The methylation status of primary patient samples was determined by MBD-Cap sequencing. Lastly, the clinical prognostic significance of miR-184 putative targets was assessed using publicly available datasets.
A large number of microRNA were restricted in their expression to specific tissue subsets. MicroRNA-184 (miR-184) was exclusively expressed in epithelial cells and markedly upregulated during differentiation of the proliferative, invasive cells of the pubertal terminal end bud (TEB) into ductal epithelial cells in vivo. miR-184 expression was silenced in mouse tumour models compared to non-transformed epithelium and in a majority of breast cancer cell line models. Ectopic reactivation of miR-184 inhibited the proliferation and self-renewal of triple negative breast cancer (TNBC) cell lines in vitro and delayed primary tumour formation and reduced metastatic burden in vivo. Gene expression studies uncovered multi-factorial regulation of genes in the AKT/mTORC1 pathway by miR-184. In clinical breast cancer tissues, expression of miR-184 is lost in primary TNBCs while the miR-184 promoter is methylated in a subset of lymph node metastases from TNBC patients.
These studies elucidate a new layer of regulation in the PI3K/AKT/mTOR pathway with relevance to mammary development and tumour progression and identify miR-184 as a putative breast tumour suppressor.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0593-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4504458  PMID: 26070602
2.  New insights into the role of ID proteins in breast cancer metastasis: a MET affair 
The establishment of lethal metastases depends on the capacity of a small number of cancer cells to regenerate a tumor after entering a target organ. Stankic and colleagues have identified a role for the inhibitor of differentiation protein, ID1, as a critical regulator of breast cancer stem-like properties and metastatic colonization. Under the control of tumor growth factor-beta signaling, ID1 induces mesenchymal-epithelial transition at the metastatic site by antagonizing the activity of the basic helix-loop-helix transcription factor Twist1. This study sheds light on mechanisms that initiate metastatic outgrowth, and strengthens the concept that epithelial-mesenchymal plasticity is crucial at different stages of metastasis.
PMCID: PMC4053215  PMID: 25927844
3.  Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signalling networks and conserved oncogenic pathways 
Although aberrant tyrosine kinase signalling characterises particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken to date. This may identify conserved oncogenic pathways and potential therapeutic targets.
We applied an immunoaffinity/mass spectrometry workflow to three mouse models: murine stem cell virus-Neu, expressing truncated Neu, the rat orthologue of human epidermal growth factor receptor 2, Her2 (HER2); mouse mammary tumour virus-polyoma virus middle T antigen (PyMT); and the p53−/− transplant model (p53). Pathways and protein–protein interaction networks were identified by bioinformatics analysis. Molecular mechanisms underpinning differences in tyrosine phosphorylation were characterised by Western blot analysis and array comparative genomic hybridisation. The functional role of mesenchymal–epithelial transition factor (Met) in a subset of p53-null tumours was interrogated using a selective tyrosine kinase inhibitor (TKI), small interfering RNA (siRNA)–mediated knockdown and cell proliferation assays.
The three models could be distinguished on the basis of tyrosine phosphorylation signatures and signalling networks. HER2 tumours exhibited a protein–protein interaction network centred on avian erythroblastic leukaemia viral oncogene homologue 2 (Erbb2), epidermal growth factor receptor and platelet-derived growth factor receptor α, and they displayed enhanced tyrosine phosphorylation of ERBB receptor feedback inhibitor 1. In contrast, the PyMT network displayed significant enrichment for components of the phosphatidylinositol 3-kinase signalling pathway, whereas p53 tumours exhibited increased tyrosine phosphorylation of Met and components or regulators of the cytoskeleton and shared signalling network characteristics with basal and claudin-low breast cancer cells. A subset of p53 tumours displayed markedly elevated cellular tyrosine phosphorylation and Met expression, as well as Met gene amplification. Treatment of cultured p53-null cells exhibiting Met amplification with a selective Met TKI abrogated aberrant tyrosine phosphorylation and blocked cell proliferation. The effects on proliferation were recapitulated when Met was knocked down using siRNA. Additional subtypes of p53 tumours exhibited increased tyrosine phosphorylation of other oncogenes, including Peak1/SgK269 and Prex2.
This study provides network-level insights into signalling in the breast cancer models utilised and demonstrates that comparative phosphoproteomics can identify conserved oncogenic signalling pathways. The Met-amplified, p53-null tumours provide a new preclinical model for a subset of triple-negative breast cancers.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0437-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4303118  PMID: 25200860
4.  The Hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy 
Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.
PMCID: PMC3672663  PMID: 23547970
5.  Interleukin-27 Signaling Promotes Immunity against Endogenously Arising Murine Tumors 
PLoS ONE  2013;8(3):e57469.
Interleukin-27 (IL-27) is a pleiotropic cytokine but its immunosuppressive effects predominate during many in vivo immunological challenges. Despite this, evidence from tumor cell line transfer models suggested that IL-27 could promote immune responses in the tumor context. However, the role of IL-27 in immunity against tumors that develop in situ and in tumor immunosurveillance remain undefined. In this study, we demonstrate that tumor development and growth are accelerated in IL-27 receptor α (Il27ra)-deficient mice. Enhanced tumor growth in both carcinogen-induced fibrosarcoma and oncogene-driven mammary carcinoma was associated with decreased interferon-γ production by CD4 and CD8 T cells and increased numbers of regulatory T-cells (Treg). This is the first study to show that IL-27 promotes protective immune responses against endogenous tumors, which is critical as the basis for future development of an IL-27 based therapeutic agent.
PMCID: PMC3595259  PMID: 23554861
6.  Prevalence of Dyslipidemia and Lipid Goal Attainment in Statin-Treated Subjects From 3 Data Sources: A Retrospective Analysis 
Evidence-based randomized clinical trials have shown significant benefit of statin treatment with regard to cardiovascular disease. In anticipation of the National Cholesterol Education Program Adult Treatment Panel IV guidelines, we wanted to assess the current state of lipid goal attainment in the high-risk secondary prevention population in the United States. The objectives of the study were to estimate the proportion of high-risk patients treated with statin monotherapy who achieved Adult Treatment Panel III–recommended low-density lipoprotein cholesterol (LDL-C) goals (<100 mg/dL; optional <70 mg/dL) as well as non–high-density lipoprotein cholesterol goals (<130 mg/dL; optional <100 mg/dL).
Methods and Results
This is a cross-sectional, retrospective study of 3 data sources: electronic medical records (2003–September 2010), administrative claims data (2003–2010), and National Health and Nutrition Examination Survey data (2007–2008). High-risk patients (≥18 years of age) were defined as those with a history of coronary heart disease or coronary heart disease risk equivalent who had the latest complete lipid panel measurement and had been treated with statin monotherapy for >90 days at the time of the lipid panel. Cardiovascular disease, coronary heart disease, and coronary heart disease risk equivalents were defined on the basis of availability, specific to each data source. Across the 3 data sources, 20% to 26% of high-risk patients treated with statin monotherapy for >90 days had LDL-C <70 mg/dL, and 67% to 77% had LDL-C <100 mg/dL. The percentages of those attaining both LDL-C goals and non–high-density lipoprotein cholesterol goals were quantitatively smaller (13.5% to 19.0% and 46% to 70%).
Across the 3 data sources, there was consistency in the proportion of high-risk patients treated with statin monotherapy who were at LDL-C goal. A significant number of these statin-treated patients had additional dyslipidemias.
PMCID: PMC3540660  PMID: 23316314
coronary heart disease; dyslipidemia; low-density lipoprotein cholesterol; non–high-density lipoprotein cholesterol; statins
7.  BioEve Search: A Novel Framework to Facilitate Interactive Literature Search 
Advances in Bioinformatics  2012;2012:509126.
Background. Recent advances in computational and biological methods in last two decades have remarkably changed the scale of biomedical research and with it began the unprecedented growth in both the production of biomedical data and amount of published literature discussing it. An automated extraction system coupled with a cognitive search and navigation service over these document collections would not only save time and effort, but also pave the way to discover hitherto unknown information implicitly conveyed in the texts. Results. We developed a novel framework (named “BioEve”) that seamlessly integrates Faceted Search (Information Retrieval) with Information Extraction module to provide an interactive search experience for the researchers in life sciences. It enables guided step-by-step search query refinement, by suggesting concepts and entities (like genes, drugs, and diseases) to quickly filter and modify search direction, and thereby facilitating an enriched paradigm where user can discover related concepts and keywords to search while information seeking. Conclusions. The BioEve Search framework makes it easier to enable scalable interactive search over large collection of textual articles and to discover knowledge hidden in thousands of biomedical literature articles with ease.
PMCID: PMC3368157  PMID: 22693501
8.  Redefining the Expression and Function of the Inhibitor of Differentiation 1 in Mammary Gland Development 
PLoS ONE  2010;5(8):e11947.
The accumulation of poorly differentiated cells is a hallmark of breast neoplasia and progression. Thus an understanding of the factors controlling mammary differentiation is critical to a proper understanding of breast tumourigenesis. The Inhibitor of Differentiation 1 (Id1) protein has well documented roles in the control of mammary epithelial differentiation and proliferation in vitro and breast cancer progression in vivo. However, it has not been determined whether Id1 expression is sufficient for the inhibition of mammary epithelial differentiation or the promotion of neoplastic transformation in vivo. We now show that Id1 is not commonly expressed by the luminal mammary epithelia, as previously reported. Generation and analysis of a transgenic mouse model of Id1 overexpression in the mammary gland reveals that Id1 is insufficient for neoplastic progression in virgin animals or to prevent terminal differentiation of the luminal epithelia during pregnancy and lactation. Together, these data demonstrate that there is no luminal cell-autonomous role for Id1 in mammary epithelial cell fate determination, ductal morphogenesis and terminal differentiation.
PMCID: PMC2914758  PMID: 20689821

Results 1-8 (8)