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Sökning: WFRF:(De Marchi Tommaso)

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1.
  • Liu, Ning Qing, et al. (författare)
  • Comparative proteome analysis revealing an 11-protein signature for aggressive triple-negative breast cancer
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 1460-2105. ; 106:2
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Clinical outcome of patients with triple-negative breast cancer (TNBC) is highly variable. This study aims to identify and validate a prognostic protein signature for TNBC patients to reduce unnecessary adjuvant systemic therapy.METHODS: Frozen primary tumors were collected from 126 lymph node-negative and adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling in two series: an in-house training (n = 63) and a multicenter test (n = 63) set. Patients who remained free of distant metastasis for a minimum of 5 years after surgery were defined as having good prognosis. Cox regression analysis was performed to develop a prognostic signature, which was independently validated. All statistical tests were two-sided.RESULTS: An 11-protein signature was developed in the training set (median follow-up for good-prognosis patients = 117 months) and subsequently validated in the test set (median follow-up for good-prognosis patients = 108 months) showing 89.5% sensitivity (95% confidence interval [CI] = 69.2% to 98.1%), 70.5% specificity (95% CI = 61.7% to 74.2%), 56.7% positive predictive value (95% CI = 43.8% to 62.1%), and 93.9% negative predictive value (95% CI = 82.3% to 98.9%) for poor-prognosis patients. The predicted poor-prognosis patients had higher risk to develop distant metastasis than the predicted good-prognosis patients in univariate (hazard ratio [HR] = 13.15; 95% CI = 3.03 to 57.07; P = .001) and multivariable (HR = 12.45; 95% CI = 2.67 to 58.11; P = .001) analysis. Furthermore, the predicted poor-prognosis group had statistically significantly more breast cancer-specific mortality. Using our signature as guidance, more than 60% of patients would have been exempted from unnecessary adjuvant chemotherapy compared with conventional prognostic guidelines.CONCLUSIONS: We report the first validated proteomic signature to assess the natural course of clinical TNBC.
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2.
  • Benedetti, Rosaria, et al. (författare)
  • Inhibition of histone demethylases LSD1 and UTX regulates ERα signaling in breast cancer
  • 2019
  • Ingår i: Cancers. - : Multidisciplinary Digital Publishing Institute (MDPI). - 2072-6694. ; 11:12
  • Tidskriftsartikel (refereegranskat)abstract
    • In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.
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3.
  • De Marchi, Tommaso, et al. (författare)
  • 4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer
  • Ingår i: Molecular Oncology. - : Elsevier. - 1574-7891. ; 10:1, s. 24-39
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth proteome analyses have enabled identification of clinically useful biomarkers, particularly, when heterogeneity in complex tumor tissue was reduced using laser capture microdissection (LCM). In the current study, we performed high resolution proteomic analysis on two cohorts of ER positive breast tumors derived from patients who either manifested good or poor outcome to tamoxifen treatment upon recurrence. A total of 112 fresh frozen tumors were collected from multiple medical centers and divided into two sets: an in-house training and a multi-center test set. Epithelial tumor cells were enriched with LCM and analyzed by nano-LC Orbitrap mass spectrometry (MS), which yielded >3000 and >4000 quantified proteins in the training and test sets, respectively. Raw data are available via ProteomeXchange with identifiers PXD000484 and PXD000485. Statistical analysis showed differential abundance of 99 proteins, of which a subset of 4 proteins was selected through a multivariate step-down to develop a predictor for tamoxifen treatment outcome. The 4-protein signature significantly predicted poor outcome patients in the test set, independent of predictive histopathological characteristics (hazard ratio [HR] = 2.17; 95% confidence interval [CI] = 1.15 to 4.17; multivariate Cox regression p value = 0.017). Immunohistochemical (IHC) staining of PDCD4, one of the signature proteins, on an independent set of formalin-fixed paraffin-embedded tumor tissues provided and independent technical validation (HR = 0.72; 95% CI = 0.57 to 0.92; multivariate Cox regression p value = 0.009). We hereby report the first validated protein predictor for tamoxifen treatment outcome in recurrent ER-positive breast cancer. IHC further showed that PDCD4 is an independent marker.
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4.
  • De Marchi, Tommaso, et al. (författare)
  • Annexin-A1 and caldesmon are associated with resistance to tamoxifen in estrogen receptor positive recurrent breast cancer
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:3, s. 3098-3110
  • Tidskriftsartikel (refereegranskat)abstract
    • Tamoxifen therapy resistance constitutes a major cause of death in patients with recurrent estrogen receptor (ER) positive breast cancer. Through high resolution mass spectrometry (MS), we previously generated a 4-protein predictive signature for tamoxifen therapy outcome in recurrent breast cancer. ANXA1 and CALD1, which were not included in the classifier, were however the most differentially expressed proteins. We first evaluated the clinical relevance of these markers in our MS cohort, followed by immunohistochemical (IHC) staining on an independent set of tumors incorporated in a tissue microarray (TMA) and regression analysis in relation to time to progression (TTP), clinical benefit and objective response. In order to assess which mechanisms ANXA1 and CALD1 might been involved in, we performed Ingenuity pathway analysis (IPA) on ANXA1 and CALD1 correlated proteins in our MS cohort. ANXA1 (Hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.22-2.75; P = 0.003) and CALD1 (HR = 1.57; 95% CI: 1.04-2.36; P = 0.039) based patient stratification showed significant association to TTP, while IHC staining on TMA showed that both ANXA1 (HR = 1.82; 95% CI: 1.12-3.00; P = 0.016) and CALD1 (HR = 2.29; 95% CI: 1.40-3.75; P = 0.001) expression was associated with shorter TTP independently of traditional predictive factors. Pearson correlation analysis showed that the majority of proteins correlated to ANXA1 also correlated with CALD1. IPA indicated that ANXA1 and CALD1 were associated with ER-downregulation and NFκB signaling. We hereby report that ANXA1 and CALD1 proteins are independent markers for tamoxifen therapy outcome and are associated to fast tumor progression.
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5.
  • De Marchi, Tommaso, et al. (författare)
  • Antibody-based capture of target peptides in multiple reaction monitoring experiments
  • 2015
  • Ingår i: Mammary Stem Cells : Methods and Protocols - Methods and Protocols. - : Humana Press. ; 1293, s. 35-123
  • Bokkapitel (refereegranskat)abstract
    • Targeted quantitative mass spectrometry of immunoaffinity-enriched peptides, termed immuno-multiple reaction monitoring (iMRM), is a powerful method for determining the relative abundance of proteins in complex mixtures, like plasma or whole tissue. This technique combines 1,000-fold enrichment potential of antibodies for target peptides with the selectivity of multiple reaction monitoring mass spectrometry (MRM-MS). Using heavy isotope-labeled peptide counterparts as internal standards ensures high levels of precision. Further, LC-MRM-MS selectivity allows for multiplexing; antibodies recognizing different peptides can be added directly to a single mixture without subjecting to interferences common to other multiple antibody protein assays. Integrated extracted ion chromatograms (XIC) of product ions from endogenous unlabeled "light" peptide and stable isotope-labeled internal standard "heavy" peptides are used to generate a light/heavy peak area ratio. This ratio is proportional to the amount of peptide in the digestion mixture and can be used to estimate the concentration of protein in the sample.
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6.
  • De Marchi, Tommaso, et al. (författare)
  • Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer
  • Ingår i: Drug Discovery Today. - : Elsevier. - 1878-5832. ; 21:7, s. 8-1181
  • Forskningsöversikt (refereegranskat)abstract
    • Estrogen receptor (ER)-positive breast cancer represents the majority (∼70%) of all breast malignancies. In this subgroup of breast cancers, endocrine therapies are effective both in the adjuvant and recurrent settings, although resistance remains a major issue. Several high-throughput approaches have been used to elucidate mechanisms of resistance and to derive potential predictive markers or alternative therapies. In this review, we cover the state-of-the-art of endocrine-resistance biomarker discovery with regard to the latest technological developments, and discuss current opportunities and restrictions for their implementation into a clinical setting.
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7.
  • De Marchi, Tommaso, et al. (författare)
  • Global proteomic characterization of microdissected estrogen receptor positive breast tumors
  • Ingår i: Data in Brief. - : Elsevier. - 2352-3409. ; 5, s. 399-402
  • Tidskriftsartikel (refereegranskat)abstract
    • We here describe two proteomic datasets deposited in ProteomeXchange via PRIDE partner repository [1] with dataset identifiers PXD000484 (defined as "training") and PXD000485 (defined as "test") that have been used for the development of a tamoxifen outcome predictive signature [2]. Both datasets comprised 56 fresh frozen estrogen receptor (ER) positive primary breast tumor specimens derived from patients who received tamoxifen as first line therapy for recurrent disease. Patient groups were defined based on time to progression (TTP) after start of tamoxifen therapy (6 months cutoff): 32 good and 24 poor treatment outcome patients were comprised in the training set, respectively. The test set included 41 good and 15 poor treatment outcome patients. All specimens were subjected to laser capture microdissection (LCM) to enrich for epithelial tumor cells prior to high resolution mass spectrometric (MS) analysis. Protein identification and label-free quantification (LFQ) were performed with MaxQuant software package [3]. A total of 3109 and 4061 proteins were identified and quantified in the training and test set, respectively. We here present the first public proteomic dataset analyzing ER positive recurrent breast cancer by LCM coupled to high resolution MS.
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8.
  • De Marchi, Tommaso, et al. (författare)
  • Phosphoserine aminotransferase 1 is associated to poor outcome on tamoxifen therapy in recurrent breast cancer
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In a previous study, we detected a significant association between phosphoserine aminotransferase 1 (PSAT1) hyper-methylation and mRNA levels to outcome to tamoxifen treatment in recurrent disease. We here aimed to study the association of PSAT1 protein levels to outcome upon tamoxifen treatment and to obtain more insight in its role in tamoxifen resistance. A cohort of ER positive, hormonal therapy naïve primary breast carcinomas was immunohistochemically (IHC) stained for PSAT1. Staining was analyzed for association with patient's time to progression (TTP) and overall response on first-line tamoxifen for recurrent disease. PSAT1 mRNA levels were also assessed by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR; n = 161) and Affymetrix GeneChip (n = 155). Association of PSAT1 to biological pathways on tamoxifen outcome were assessed by global test. PSAT1 protein and mRNA levels were significantly associated to poor outcome to tamoxifen treatment. When comparing PSAT1 protein and mRNA levels, IHC and RT-qPCR data showed a significant association. Global test results showed that cytokine and JAK-STAT signaling were associated to PSAT1 expression. We hereby report that PSAT1 protein and mRNA levels measured in ER positive primary tumors are associated with poor clinical outcome to tamoxifen.
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9.
  • De Marchi, Tommaso, et al. (författare)
  • Targeted MS Assay Predicting Tamoxifen Resistance in Estrogen-Receptor-Positive Breast Cancer Tissues and Sera
  • Ingår i: Journal of Proteome Research. - : The American Chemical Society (ACS). - 1535-3893. ; 15:4, s. 42-1230
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently reported on the development of a 4-protein-based classifier (PDCD4, CGN, G3BP2, and OCIAD1) capable of predicting outcome to tamoxifen treatment in recurrent, estrogen-receptor-positive breast cancer based on high-resolution MS data. A precise and high-throughput assay to measure these proteins in a multiplexed, targeted fashion would be favorable to measure large numbers of patient samples to move these findings toward a clinical setting. By coupling immunoprecipitation to multiple reaction monitoring (MRM) MS and stable isotope dilution, we developed a high-precision assay to measure the 4-protein signature in 38 primary breast cancer whole tissue lysates (WTLs). Furthermore, we evaluated the presence and patient stratification capabilities of our signature in an independent set of 24 matched (pre- and post-therapy) sera. We compared the performance of immuno-MRM (iMRM) with direct MRM in the absence of fractionation and shotgun proteomics in combination with label-free quantification (LFQ) on both WTL and laser capture microdissected (LCM) tissues. Measurement of the 4-proteins by iMRM showed not only higher accuracy in measuring proteotypic peptides (Spearman r: 0.74 to 0.93) when compared with MRM (Spearman r: 0.0 to 0.76) but also significantly discriminated patient groups based on treatment outcome (hazard ratio [HR]: 10.96; 95% confidence interval [CI]: 4.33 to 27.76; Log-rank P < 0.001) when compared with LCM (HR: 2.85; 95% CI: 1.24 to 6.54; Log-rank P = 0.013) and WTL (HR: 1.16; 95% CI: 0.57 to 2.33; Log-rank P = 0.680) LFQ-based predictors. Serum sample analysis by iMRM confirmed the detection of the four proteins in these samples. We hereby report that iMRM outperformed regular MRM, confirmed our previous high-resolution MS results in tumor tissues, and has shown that the 4-protein signature is measurable in serum samples.
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10.
  • De Marchi, Tommaso, et al. (författare)
  • The advantage of laser-capture microdissection over whole tissue analysis in proteomic profiling studies
  • Ingår i: Proteomics. - : John Wiley and Sons Inc.. - 1615-9861. ; 16:10, s. 85-1474
  • Tidskriftsartikel (refereegranskat)abstract
    • Laser-capture microdissection (LCM) offers a reliable cell population enrichment tool and has been successfully coupled to MS analysis. Despite this, most proteomic studies employ whole tissue lysate (WTL) analysis in the discovery of disease biomarkers and in profiling analyses. Furthermore, the influence of tissue heterogeneity in WTL analysis, nor its impact in biomarker discovery studies have been completely elucidated. In order to address this, we compared previously obtained high resolution MS data from a cohort of 38 breast cancer tissues, of which both LCM enriched tumor epithelial cells and WTL samples were analyzed. Label-free quantification (LFQ) analysis through MaxQuant software showed a significantly higher number of identified and quantified proteins in LCM enriched samples (3404) compared to WTLs (2837). Furthermore, WTL samples displayed a higher amount of missing data compared to LCM both at peptide and protein levels (p-value < 0.001). 2D analysis on co-expressed proteins revealed discrepant expression of immune system and lipid metabolisms related proteins between LCM and WTL samples. We hereby show that LCM better dissected the biology of breast tumor epithelial cells, possibly due to lower interference from surrounding tissues and highly abundant proteins. All data have been deposited in the ProteomeXchange with the dataset identifier PXD002381 (http://proteomecentral.proteomexchange.org/dataset/PXD002381).
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