Common Molecular Mechanisms of Mammary Gland Development and Breast Cancer

During its lifetime, the mammary gland undergoes many phases of development and differentiation. Much of this occurs during puberty, when the ductal epithelium expands by branching morphogenesis, invading the surrounding fat pad to form an organised mammary tree. Throughout its existence, the epithelium will go through several cycles of proliferation and cell death during pregnancy, lactation and involution. Many of the signalling mechanisms which control the initial invasion of the fat pad by the epithelium, and regulate its continuing plasticity, can be harnessed or corrupted by tumour cells in order to support their aberrant growth and progression towards invasion. This is true not just for the epithelial cells themselves but also for cells in the surrounding microenvironment, including fibroblasts, macrophages and adipocytes. This review examines the complex web of signalling and adhesion interactions controlling branching morphogenesis, and how their alteration can promote malignancy. Current in vivo and in vitro mammary gland models are also discussed. (Part of a Multi-author Review)     

The molecular role of the Rothmund-Thomson-, RAPADILINO- and Baller-Gerold-gene product, RECQL4: recent progress

The RecQ family of DNA helicases is highly conserved throughout evolution and plays an important role in the maintenance of genomic stability in all organisms. Mutations in three of the five known family members in humans, BLM, WRN and RECQL4, give rise to disorders that are characterized by predisposition to cancer and premature aging, emphasizing the importance of studying the RecQ proteins and their cellular activities. Interestingly, three autosomal recessive disorders have been associated with mutations in the RECQL4 gene: Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes, thus making RECQL4 unique within the RecQ family of DNA helicases. To date, however, the molecular function of RECQL4 and the possible cellular pathways in which it is involved remain poorly understood. Here, we present an overview of recent findings in connection with RECQL4 and try to highlight different directions the field could head, helping to clarify the role of RECQL4 in preventing tumorigenesis and maintenance of genome integrity in humans. Received 31 October 2006; received after revision 4 January 2007; accepted 5 February 2007     

Computational protein function prediction: Are we making progress?

The computational prediction of gene and protein function is rapidly gaining ground as a central undertaking in computational biology. Making sense of the flood of genomic data requires fast and reliable annotation. Many ingenious algorithms have been devised to infer a protein's function from its amino acid sequence, 3D structure and chromosomal location of the encoding genes. However, there are significant challenges in assessing how well these programs perform. In this article we explore those challenges and review our own attempt at assessing the performance of those programs. We conclude that the task is far from complete and that a critical assessment of the performance of function prediction programs is necessary to make true progress in computational function prediction.     

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner's syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner's syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed.     

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, K-Ras4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform-specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancer and may suggest new therapeutic approaches.     

Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate

Numerous microRNAs (miRNAs) have been discovered in the genomes of higher eukaryotes, and functional studies indicate that they are important during development. However, little is known concerning the function of individual miRNAs. We approached this problem in zebrafish by combining identification of miRNA expression, functional analyses and experimental validation of potential targets. We show that miR-214 is expressed during early segmentation stages in somites and that varying its expression alters the expression of genes regulated by Hedgehog signaling. Inhibition of miR-214 results in a reduction or loss of slow-muscle cell types. We show that su(fu) mRNA, encoding a negative regulator of Hedgehog signaling, is targeted by miR-214. Through regulation of su(fu), miR-214 enables precise specification of muscle cell types by sharpening cellular responses to Hedgehog.     

Germline gain-of-function mutations in SOS1 cause Noonan syndrome

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.     

Variation in FTO contributes to childhood obesity and severe adult obesity

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.     

The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast

The autosomal recessive disorder Shwachman-Diamond syndrome, characterized by bone marrow failure and leukemia predisposition, is caused by deficiency of the highly conserved Shwachman-Bodian-Diamond syndrome (SBDS) protein. Here, we identify the function of the yeast SBDS ortholog Sdo1, showing that it is critical for the release and recycling of the nucleolar shuttling factor Tif6 from pre-60S ribosomes, a key step in 60S maturation and translational activation of ribosomes. Using genome-wide synthetic genetic array mapping, we identified multiple TIF6 gain-of-function alleles that suppressed the pre-60S nuclear export defects and cytoplasmic mislocalization of Tif6 observed in sdo1Delta cells. Sdo1 appears to function within a pathway containing elongation factor-like 1, and together they control translational activation of ribosomes. Thus, our data link defective late 60S ribosomal subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition.