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News Article | February 15, 2017
Site: www.medicalnewstoday.com

Walter and Eliza Hall Institute researchers have used advanced cellular, bioinformatics and imaging technology to reveal a long-lived type of stem cell in the breast that is responsible for the growth of the mammary glands during pregnancy. The newly discovered stem cells, which respond to the 'ovarian hormones' progesterone and oestrogen, may also be linked to a high-risk form of breast cancer. The discovery was made by Dr Nai Yang Fu, Dr Anne Rios, Professor Jane Visvader and Professor Geoff Lindeman as part of a 20-year research program into how the breast develops from stem cells, and how breast cancers can arise from stem cells and developing breast tissue. The research was published in Nature Cell Biology. Dr Fu said the team had been able to build on their earlier discovery of breast stem cells, by defining subsets of stem cells with different functions, a project that was conducted in collaboration with bioinformatics researchers Dr Matthew Ritchie and Professor Gordon Smyth. "When we looked at the genes that were switched on in these stem cells, we could distinguish subsets of stem cells that differed in their expression of genes encoding two proteins called Tetraspanin8 and Lgr5," he said. "By looking at the levels of Tetraspanin8 and Lgr5 protein on the surface of the cells, we could divide the stem cells into three separate groups." The team used advanced technologies including three-dimensional imaging to show that the three groups of stem cells are located in different parts of the breast and function differently, Dr Rios said. "We focused particularly on one stem cell subtype that had the highest levels of Tetraspanin8 and Lgr5 protein, which were located in the 'proximal' region of the breast around the nipple," Dr Rios said. Professor Visvader said these stem cells were normally dormant - sitting quietly and not dividing - and remained in the proximal region throughout life. "However, when they were exposed to the hormones progesterone and oestrogen these cells awakened and could rapidly give rise to new breast cells," she said. The research also revealed that the stem cells with high levels of Tetraspanin8 and Lgr5 protein had many similarities to a subtype of 'triple negative' breast cancers known as claudin-low cancers. "Compared to other types of breast cancer, claudin-low cancers have a high chance of recurrence after treatment, leading to a poor prognosis for patients" Professor Visvader said. Professor Lindeman, who is also a medical oncologist at the Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, said the research may lead to future improved outcomes for people with claudin-low cancers, "We hope that our discovery can be used to understand how cancers may arise from long-lived stem cells, and potentially lead to better outcomes for breast cancer patients in the future," he said. The research was supported by the National Health and Medical Research Council, the Australian Cancer Research Foundation, The Qualtrough Cancer Research Fund, the Joan Marshall Breast Cancer Research Fund, the National Breast Cancer Foundation, Cure Cancer Australia, the Victorian Cancer Agency and the Victorian Government Operational Infrastructure Support Scheme. Article: Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive, Nai Yang Fu, Anne C. Rios, Bhupinder Pal, Charity W. Law, Paul Jamieson, Ruijie Liu, François Vaillant, Felicity Jackling, Kevin He Liu, Gordon K. Smyth, Geoffrey J. Lindeman, Matthew E. Ritchie & Jane E. Visvader, Nature Cell Biology, doi: 10.1038/ncb3471, published online 13 February 2017.


Blewitt M.,Walter and Eliza Hall Institute | Whitelaw E.,Queensland Institute of Medical Research
Cold Spring Harbor Perspectives in Biology | Year: 2013

Much of what we know about the role of epigenetics in the determination of phenotype has come from studies of inbred mice. Some unusual expression patterns arising fromendogenous and transgenic murine alleles, such as the Agouti coat color alleles, have allowed the study of variegation, variable expressivity, transgenerational epigenetic inheritance, parent-of-origin effects, and position effects. These phenomena have taught us much about gene silencing and the probabilistic nature of epigenetic processes. Based on some of these alleles, large-scale mutagenesis screens have broadened our knowledge of epigenetic control by identifying and characterizing novel genes involved in these processes. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Robinson M.D.,Walter and Eliza Hall Institute | Robinson M.D.,Garvan Institute of Medical Research | Oshlack A.,Walter and Eliza Hall Institute
Genome Biology | Year: 2010

The fine detail provided by sequencing-based transcriptome surveys suggests that RNA-seq is likely to become the platform of choice for interrogating steady state RNA. In order to discover biologically important changes in expression, we show that normalization continues to be an essential step in the analysis. We outline a simple and effective method for performing normalization and show dramatically improved results for inferring differential expression in simulated and publicly available data sets. © 2010 Robinson and Oshlack; licensee BioMed Central Ltd.


Benjamini Y.,University of California at Berkeley | Speed T.P.,University of California at Berkeley | Speed T.P.,Walter and Eliza Hall Institute
Nucleic Acids Research | Year: 2012

GC content bias describes the dependence between fragment count (read coverage) and GC content found in Illumina sequencing data. This bias can dominate the signal of interest for analyses that focus on measuring fragment abundance within a genome, such as copy number estimation (DNA-seq). The bias is not consistent between samples; and there is no consensus as to the best methods to remove it in a single sample. We analyze regularities in the GC bias patterns, and find a compact description for this unimodal curve family. It is the GC content of the full DNA fragment, not only the sequenced read, that most influences fragment count. This GC effect is unimodal: both GC-rich fragments and AT-rich fragments are underrepresented in the sequencing results. This empirical evidence strengthens the hypothesis that PCR is the most important cause of the GC bias. We propose a model that produces predictions at the base pair level, allowing strand-specific GC-effect correction regardless of the downstream smoothing or binning. These GC modeling considerations can inform other high-throughput sequencing analyses such as ChIP-seq and RNA-seq. © 2011 The Author(s).


Blewitt M.,Walter and Eliza Hall Institute
Cold Spring Harbor perspectives in biology | Year: 2013

Much of what we know about the role of epigenetics in the determination of phenotype has come from studies of inbred mice. Some unusual expression patterns arising from endogenous and transgenic murine alleles, such as the Agouti coat color alleles, have allowed the study of variegation, variable expressivity, transgenerational epigenetic inheritance, parent-of-origin effects, and position effects. These phenomena have taught us much about gene silencing and the probabilistic nature of epigenetic processes. Based on some of these alleles, large-scale mutagenesis screens have broadened our knowledge of epigenetic control by identifying and characterizing novel genes involved in these processes.


Buchert M.,Walter and Eliza Hall Institute
Oncogene | Year: 2015

Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families. Therapeutic inhibition of the JAK/STAT3 pathway potentially offers considerable benefit owing to the capacity of JAK/STAT3 signaling to promote cancer hallmarks in the tumor and its environment, including proliferation, survival, angiogenesis, tumor metabolism while suppressing antitumor immunity. This is further emphasized by the current successful clinical applications of JAK-specific small molecule inhibitors for the treatment of inflammatory disorders and hematopoietic malignancies. Here we review current preclinical applications for JAK inhibitors for the treatment of solid cancers in mice, with a focus on the most common malignancies emanating from oncogenic transformation of the epithelial mucosa in the stomach and colon. Emerging data with small molecule JAK-specific adenosine triphosphate-binding analogs corroborate genetic findings and suggest that interference with the JAK/STAT3 pathway may suppress the growth of the most common forms of sporadic colon cancers that arise from mutations of the APC tumor suppressor gene. Likewise inhibition of cytokine-dependent activation of the JAK/STAT3 pathway may also afford orthogonal treatment opportunities for other oncogene-addicted cancer cells that have gained drug resistance.Oncogene advance online publication, 18 May 2015; doi:10.1038/onc.2015.150. © 2015 Macmillan Publishers Limited


Huntington N.D.,Walter and Eliza Hall Institute
Immunology and Cell Biology | Year: 2014

Natural killer (NK) cells are the founding members of the innate lymphoid cell family and contribute to the rapid production of inflammatory mediators upon pathogen detection. The evolution of receptors for self major histocompatibility complex-I and stress-induced ligands also bestows upon NK cells an important effector role in the clearance of virus-infected and transformed cells. NK cells are dependent on the pleiotropic cytokine interleukin (IL)-15 for their development, differentiation and optimal function. Here I review the regulation of IL-15 in vivo, its role in driving NK cell differentiation and discuss the function of NK cell diversification with regard to innate immunity. © 2014 Australasian Society for Immunology Inc.


Tarlinton D.,Walter and Eliza Hall Institute
Current Biology | Year: 2012

Three recent papers provide striking insight into the mechanisms used to regulate B-cell differentiation. They demonstrate that B-cell fate choice can be stochastic, directed, inherited, or some combination of these, depending on the circumstances. The trick is going to be working out which is important when. © 2012 Elsevier Ltd.


Silke J.,Walter and Eliza Hall Institute
Current Opinion in Immunology | Year: 2011

In the past 2 years there has been an explosion of information regarding molecules that regulate TNF-R1 signalling, and even reviews published in 2010 are out of date. TNF-R1 activation of NF-κB is a text book example of a signal transduction pathway regulated by ubiquitin and many of the concepts concerning the different roles of ubiquitin chains were first outlined in TNF-R1 signalling. What was once a very simple pathway with clearly defined roles for ubiquitin in regulating TNF-R1 signalling has, however, now become so complicated that we have 'an embarrassment of riches' [1]. The less polite might claim our pathways of TNF-R1 signalling look as complicated as a web constructed by a drug-addled spider [2]. This review will pick apart only one small strand of the web, and will address the role of ubiquitin in the activation of NF-κB by TNF with a focus on interpreting in vivo results. Nevertheless some of the concepts, for example the role of linear ubiquitin chains in regulating signalling, may be applicable to the family in general. © 2011 Elsevier Ltd.


Vaux D.L.,Walter and Eliza Hall Institute
Annual review of cell and developmental biology | Year: 2014

The physicist Ernest Rutherford said, "If your experiment needs statistics, you ought to have done a better experiment." Although this aphorism remains true for much of today's research in cell biology, a basic understanding of statistics can be useful to cell biologists to help in monitoring the conduct of their experiments, in interpreting the results, in presenting them in publications, and when critically evaluating research by others. However, training in statistics is often focused on the sophisticated needs of clinical researchers, psychologists, and epidemiologists, whose conclusions depend wholly on statistics, rather than the practical needs of cell biologists, whose experiments often provide evidence that is not statistical in nature. This review describes some of the basic statistical principles that may be of use to experimental biologists, but it does not cover the sophisticated statistics needed for papers that contain evidence of no other kind.

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