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Differential expression of genes involved in the epigenetic regulation of cell identity in normal human mammary cell commitment and differentiation

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Chinese Journal of Cancer 2014年第10期33卷 501-510页

作者： Danila Coradini patrizia boracchi Saro Oriana Elia Biganzoli Federico Ambrogi Department of Clinical Sciences and Community Health Medical StatisticsBiometry and BioinformaticsUniversity of MilanVia Vanzetti 5Milan 20133Italy Senology Center Ambrosiana ClinicCesano BosconeMilan 20090Italy

The establishment and maintenance of mammary epithelial cell identity depends on the activity of a group of proteins, collectively called maintenance proteins, that act as epigenetic regulators of gene transcription through DNA methylation, histone modification, and chromatin remodeling. Increasing evidence indicates that dysregulation of these crucial proteins may disrupt epithelial cell integrity and trigger breast tumor initiation. Therefore, we explored in silico the expression pattern of a panel of 369 genes known to be involved in the establishment and maintenance of epithelial cell identity and mammary gland remodeling in cell subpopulations isolated from normal human mammary tissue and selectively enriched in their content of bipotent progenitors, committed luminal progenitors, and differentiated myoepithelial or differentiated luminal cells. The results indicated that, compared to bipotent cells, differentiated myoepithelial and luminal subpopulations were both characterized by the differential expression of 4 genes involved in cell identity maintenance: CBX6 and PCGF2, encoding proteins belonging to the Polycomb group, and SMARCD3 and SMARCE1, encoding proteins belonging to the Trithorax group. In addition to these common genes, the myoepithelial phenotype was associated with the differential expression of HDAC1, which encodes histone deacetylase 1, whereas the luminal phenotype was associated with the differential expression of SMARCA4 and HAT1, which encode a Trithorax protein and histone acetylase 1, respectively. The luminal compartment was further characterized by the overexpression of ALDH1A3 and GATA3, and the down-regulation of NOTCH4 and CCNB1, with the latter suggesting a block in cell cycle progression at the G2 phase. In contrast, myoepithelial differentiation was associated with the overexpression of MYC and the down-regulation of CCNE1, with the latter suggesting a block in cell cycle progression at the G1 phase.

关键词：基因表达差异乳腺细胞分化遗传调控乳腺上皮细胞组蛋白修饰人类表观

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Epithelial cell identity in hyperplastic precursors of breast cancer

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Chinese Journal of Cancer 2015年第3期34卷 121-129页

Introduction:In the adult human breast,hyperplastic enlarged lobular unit(HELU) and atypical ductal hyperplasia(ADH) are two common abnormalities that frequently coexist with ductal carcinoma in situ(DCIS).For this reason,they have been proposed as the early steps in a biological continuum toward breast ***:We investigated in silico the expression of 369 genes experimentally recognized as involved in establishing and maintaining epithelial cell identity and mammary gland remodeling,in HELUs or ADHs with respect to the corresponding patient-matched normal ***:Despite the common luminal origin,HELUs and ADHs proved to be characterized by distinct gene profiles that overlap for 5 genes *** HELUs were associated with the overexpression of progesterone receptor(PGR),ADHs were characterized by the overexpression of estrogen receptor 1(ESR1) coupled with the overexpression of some proliferation-associated ***:This unexpected finding contradicts the notion that in differentiated luminal cells the expression of estrogen receptor(ER) is dissociated from cell proliferation and suggests that the establishing of an ER-dependent signaling is able to sustain cell proliferation in an autocrine manner as an early event in tumor *** clinical evidence indicates that only a fraction of HELUs and ADHs evolve to invasive cancer,present findings warn that exposure to synthetic progestins,frequently administered as hormone-replacement therapy,and estrogens,when abnormally produced by adipose cells and persistently present in the stroma surrounding the mammary gland,may cause these hyperplastic lesions.

关键词：上皮细胞乳腺癌增生性雌激素受体孕激素受体前体细胞增殖过度表达

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Estimation of the Piecewise Exponential Model by Bayesian P-Splines via Gibbs Sampling: Robustness and Reliability of Posterior Estimates

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Open Journal of Statistics 2016年第3期6卷 451-468页

作者： Giuseppe Marano patrizia boracchi Elia M. Biganzoli Unit of Medical Statistics Biometry and Bioinformatics Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan Italy Laboratory of Medical Statistics Biometry and Epidemiology “G. A. Maccacaro” Department of Clinical Sciences and Community Health University of Milan Milan Italy

In the investigation of disease dynamics, the effect of covariates on the hazard function is a major topic. Some recent smoothed estimation methods have been proposed, both frequentist and Bayesian, based on the relationship between penalized splines and mixed models theory. These approaches are also motivated by the possibility of using automatic procedures for determining the optimal amount of smoothing. However, estimation algorithms involve an analytically intractable hazard function, and thus require ad-hoc software routines. We propose a more user-friendly alternative, consisting in regularized estimation of piecewise exponential models by Bayesian P-splines. A further facilitation is that widespread Bayesian software, such as WinBUGS, can be used. The aim is assessing the robustness of this approach with respect to different prior functions and penalties. A large dataset from breast cancer patients, where results from validated clinical studies are available, is used as a benchmark to evaluate the reliability of the estimates. A second dataset from a small case series of sarcoma patients is used for evaluating the performances of the PE model as a tool for exploratory analysis. Concerning breast cancer data, the estimates are robust with respect to priors and penalties, and consistent with clinical knowledge. Concerning soft tissue sarcoma data, the estimates of the hazard function are sensitive with respect to the prior for the smoothing parameter, whereas the estimates of regression coefficients are robust. In conclusion, Gibbs sampling results an efficient computational strategy. The issue of the sensitivity with respect to the priors concerns only the estimates of the hazard function, and seems more likely to occur when non-large case series are investigated, calling for tailored solutions.

关键词： Survival Analysis Hazard Smoothing Bayesian P-Splines Piecewise Exponential Model Time-Dependent Effects

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Differential Expression of Genes Involved in Cell Polarity, EMT and Cell-Fate in Breast Cancer and Corresponding Normal Tissue

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Advances in Breast Cancer Research 2012年第2期1卷 12-19页

作者： Danila Coradini Federico Ambrogi Saro Oriana Elia Biganzoli patrizia boracchi Department of Clinical and Community Health Sciences Medical Statistics Biometry and Bioinformatics University of Milano Italy Senology Center Casa di Cura Ambrosiana Istituto Sacra Famiglia Cesano Boscone Milano Italy

Objectives: Cell polarity and epithelial morphology are peculiar features of cells forming the terminal ductal lobular unit, and they are early lost during neoplastic transformation because of an epithelial-mesenchymal transition (EMT). To understand these early events we analyzed a set of 125 genes related to cell polarity, EMT and cell-fate decision in 26 breast cancer specimens and corresponding patient-matched normal tissue. Methods: The difference of gene expression was explored by t-paired test. In addition, to evidence latent variables accounting for genes correlations, a Factor Analysis was applied as exploratory technique. Results: Among the 90 differentially expressed genes, those coding for cell polarity complexes, apical-junctional components and luminal cytokeratins were overexpressed in tumor samples (suggesting a terminally differentiated phenotype) whereas those coding for stemness-associated features or related with EMT were expressed in normal tissues but not in tumor samples, suggesting the persistence of stem/progenitor cells. Factor analysis confirmed these findings and indicated that the difference between tumors and normal tissues can be synthesized in three main features representative of specific molecular/morphological alterations. Conclusions: The a priori definition of a selected panel of genes and the application of an exploratory statistical approach, greatly contribute to reduce the intrinsic biological complexity of tumor specimens and to describe the difference between tumor specimens and corresponding histologically normal tissues.

关键词： Breast Cancer Cell-Fate Decision Cell Polarity Epithelial-Mesenchymal Transition Histologically Normal Tissue

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