Identification of functionally related genes using data mining and data integration: a breast cancer case study

Mosca, Ettore; Bertoli, Gloria; Piscitelli, Eleonora; Vilardo, Laura; Reinbold, Rolland; Zucchi, Ileana; Milanesi, Luciano

doi:10.1186/1471-2105-10-s12-s8

Cited by 21 publications

(18 citation statements)

References 40 publications

(38 reference statements)

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“…proliferation, migration and differentiation into hypertrophic columnar cells, as well as apoptosis, apparently regulating the choice between the different fates a cell can have. As Gli3 remains expressed in the adult mammary gland [19], it may then perhaps likewise regulate the balance between normal homeostasis and tumor growth, as supported by the recent identification of Gli3 in a primary breast tumor expression dataset [41], and similar to what has recently been reviewed for several other genes [42], [43]. Of note, despite the similarities among MRs regarding the cellular mechanisms regulating their early growth, the function of Gli3 in these mechanisms differs among the MRs, indicating MRs are not mere copies of the same structure but distinct entities, as we have suggested previously [2].…”

Section: Discussionmentioning

confidence: 93%

Ectodermal Influx and Cell Hypertrophy Provide Early Growth for All Murine Mammary Rudiments, and Are Differentially Regulated among Them by Gli3

et al. 2011

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Mammary gland development starts in utero with one or several pairs of mammary rudiments (MRs) budding from the surface ectodermal component of the mammalian embryonic skin. Mice develop five pairs, numbered MR1 to MR5 from pectoral to inguinal position. We have previously shown that Gli3Xt-J/Xt-J mutant embryos, which lack the transcription factor Gli3, do not form MR3 and MR5. We show here that two days after the MRs emerge, Gli3Xt-J/Xt-J MR1 is 20% smaller, and Gli3Xt-J/Xt-J MR2 and MR4 are 50% smaller than their wild type (wt) counterparts. Moreover, while wt MRs sink into the underlying dermis, Gli3Xt-J/Xt-J MR4 and MR2 protrude outwardly, to different extents. To understand why each of these five pairs of functionally identical organs has its own, distinct response to the absence of Gli3, we determined which cellular mechanisms regulate growth of the individual MRs, and whether and how Gli3 regulates these mechanisms. We found a 5.5 to 10.7-fold lower cell proliferation rate in wt MRs compared to their adjacent surface ectoderm, indicating that MRs do not emerge or grow via locally enhanced cell proliferation. Cell-tracing experiments showed that surface ectodermal cells are recruited toward the positions where MRs emerge, and contribute to MR growth during at least two days. During the second day of MR development, peripheral cells within the MRs undergo hypertrophy, which also contributes to MR growth. Limited apoptotic cell death counterbalances MR growth. The relative contribution of each of these processes varies among the five MRs. Furthermore, each of these processes is impaired in the absence of Gli3, but to different extents in each MR. This differential involvement of Gli3 explains the variation in phenotype among Gli3Xt-J/Xt-J MRs, and may help to understand the variation in numbers and positions of mammary glands among mammals.

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Section: Discussionmentioning

confidence: 93%

Ectodermal Influx and Cell Hypertrophy Provide Early Growth for All Murine Mammary Rudiments, and Are Differentially Regulated among Them by Gli3

et al. 2011

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“…In this respect MCL has been shown to perform as well or better than other network clustering algorithms [49]. Previous efforts to identify gene signatures/modules in cancer data have used different analytical approaches, less data, grouped far fewer genes and often failed to explain the biological significance of their findings [9-11,50,51]. Where correlation networks have been used previously to analyse modularity in gene expression data [13,52], available computing frameworks have not permitted the visualization or exploration of the resultant graphs as effectively in the current study.…”

Section: Resultsmentioning

confidence: 99%

Coexpression analysis of large cancer datasets provides insight into the cellular phenotypes of the tumour microenvironment

et al. 2013

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BackgroundBiopsies taken from individual tumours exhibit extensive differences in their cellular composition due to the inherent heterogeneity of cancers and vagaries of sample collection. As a result genes expressed in specific cell types, or associated with certain biological processes are detected at widely variable levels across samples in transcriptomic analyses. This heterogeneity also means that the level of expression of genes expressed specifically in a given cell type or process, will vary in line with the number of those cells within samples or activity of the pathway, and will therefore be correlated in their expression.ResultsUsing a novel 3D network-based approach we have analysed six large human cancer microarray datasets derived from more than 1,000 individuals. Based upon this analysis, and without needing to isolate the individual cells, we have defined a broad spectrum of cell-type and pathway-specific gene signatures present in cancer expression data which were also found to be largely conserved in a number of independent datasets.ConclusionsThe conserved signature of the tumour-associated macrophage is shown to be largely-independent of tumour cell type. All stromal cell signatures have some degree of correlation with each other, since they must all be inversely correlated with the tumour component. However, viewed in the context of established tumours, the interactions between stromal components appear to be multifactorial given the level of one component e.g. vasculature, does not correlate tightly with another, such as the macrophage.

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“…These findings together imply that Tbx3 cooperates with oncogenic Ras and c-Myc by suppressing ARF activity. A recent study identified GATA3 and GLI3 as putative TBX3 downstream targets in breast cancer (68). Although chromatin immunoprecipitation analysis confirmed direct binding of TBX3 to both of these targets, the functional significance of these findings is not known.…”

Section: Tbx3 In Cancermentioning

confidence: 99%

Diverse functional networks of Tbx3 in development and disease

Washkowitz

Gavrilov

Begum

et al. 2012

WIREs Mechanisms of Disease

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The T-box transcription factor Tbx3 plays multiple roles in normal development and disease. In order to function in different tissues and on different target genes, Tbx3 binds transcription factors or other cofactors specific to temporal or spatial locations. Examining the development of the mammary gland, limbs, and heart as well as the biology of stem cells and cancer provides insights into the diverse and common functions that Tbx3 can perform. By either repressing or activating transcription of target genes in a context-dependent manner, Tbx3 is able to modulate differentiation of immature progenitor cells, control the rate of cell proliferation, and mediate cellular signaling pathways. Because the direct regulators of these cellular processes are highly context-dependent, it is essential that Tbx3 has the flexibility to regulate transcription of a large group of targets, but only become active on a small cohort of them at any given time or place. Moreover, Tbx3 must be responsive to the variety of different upstream factors that are present in different tissues. Only by understanding the network of genes, proteins, and molecules with which Tbx3 interacts can we hope to understand the role that Tbx3 plays in normal development and how its aberrant expression can lead to disease. Because of its myriad functions in disparate developmental and disease contexts, Tbx3 is an ideal candidate for a systems-based approach to genetic function and interaction.

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Identification of functionally related genes using data mining and data integration: a breast cancer case study

Cited by 21 publications

References 40 publications

Ectodermal Influx and Cell Hypertrophy Provide Early Growth for All Murine Mammary Rudiments, and Are Differentially Regulated among Them by Gli3

Ectodermal Influx and Cell Hypertrophy Provide Early Growth for All Murine Mammary Rudiments, and Are Differentially Regulated among Them by Gli3

Coexpression analysis of large cancer datasets provides insight into the cellular phenotypes of the tumour microenvironment

Diverse functional networks of Tbx3 in development and disease

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