22 results on '"Gago FE"'
Search Results
2. Primary tumour expression of the cysteine cathepsin inhibitor Stefin A inhibits distant metastasis in breast cancer
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Parker, BS, primary, Ciocca, DR, additional, Bidwell, BN, additional, Gago, FE, additional, Fanelli, MA, additional, George, J, additional, Slavin, JL, additional, Möller, A, additional, Steel, R, additional, Pouliot, N, additional, Eckhardt, BL, additional, Henderson, MA, additional, and Anderson, RL, additional
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- 2008
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3. Clinical Implications of Transcriptomic Changes After Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.
- Author
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Orozco JIJ, Grumley JG, Matsuba C, Manughian-Peter AO, Chang SC, Chang G, Gago FE, Salomon MP, and Marzese DM
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- Area Under Curve, Carcinoma, Ductal, Breast drug therapy, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast pathology, Carcinoma, Lobular drug therapy, Carcinoma, Lobular genetics, Carcinoma, Lobular pathology, Female, Follow-Up Studies, Humans, Middle Aged, Prognosis, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Gene Expression Regulation, Neoplastic drug effects, Neoadjuvant Therapy methods, Transcriptome, Triple Negative Breast Neoplasms pathology
- Abstract
Background: Pathological response to neoadjuvant chemotherapy (NAC) is critical in prognosis and selection of systemic treatments for patients with triple-negative breast cancer (TNBC). The aim of this study is to identify gene expression-based markers to predict response to NAC., Patients and Methods: A survey of 43 publicly available gene expression datasets was performed. We identified a cohort of TNBC patients treated with NAC (n = 708). Gene expression data from different studies were renormalized, and the differences between pretreatment (pre-NAC), on-treatment (post-C1), and surgical (Sx) specimens were evaluated. Euclidean statistical distances were calculated to estimate changes in gene expression patterns induced by NAC. Hierarchical clustering and pathway enrichment analyses were used to characterize relationships between differentially expressed genes and affected gene pathways. Machine learning was employed to refine a gene expression signature with the potential to predict response to NAC., Results: Forty nine genes consistently affected by NAC were involved in enhanced regulation of wound response, chemokine release, cell division, and decreased programmed cell death in residual invasive disease. The statistical distances between pre-NAC and post-C1 significantly predicted pathological complete response [area under the curve (AUC) = 0.75; p = 0.003; 95% confidence interval (CI) 0.58-0.92]. Finally, the expression of CCND1, a cyclin that forms complexes with CDK4/6 to promote the cell cycle, was the most informative feature in pre-NAC biopsies to predict response to NAC., Conclusions: The results of this study reveal significant transcriptomic changes induced by NAC and suggest that chemotherapy-induced gene expression changes observed early in therapy may be good predictors of response to NAC.
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- 2019
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4. TP73 DNA methylation and upregulation of ΔNp73 are associated with an adverse prognosis in breast cancer.
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Gomez LC, Sottile ML, Guerrero-Gimenez ME, Zoppino FCM, Redondo AL, Gago FE, Orozco JI, Tello OM, Roqué M, Nadin SB, Marzese DM, and Vargas-Roig LM
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- Breast metabolism, Breast pathology, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, DNA Methylation, Disease-Free Survival, Female, Humans, Immunohistochemistry, Prognosis, Protein Isoforms, Tumor Protein p73 metabolism, Breast Neoplasms diagnosis, Carcinoma, Ductal, Breast diagnosis, CpG Islands genetics, Tumor Protein p73 genetics
- Abstract
Aim: Accumulated evidence suggests that aberrant methylation of the TP73 gene and increased levels of ΔNp73 in primary tumours correlate with poor prognosis. However, little is known regarding the transcriptional and functional regulation of the TP73 gene in breast cancer. The aim of the present study was to determine the expression of the ΔNp73 isoform, its relationship with DNA methylation of TP73 and their clinical prognostic significance in breast cancer patients., Methods: TP73 gene methylation was studied in TCGA datasets and in 70 invasive ductal breast carcinomas (IDCs). The expression of p73 isoforms was evaluated by immunohistochemistry (IHC) and Western blot and correlated with clinicopathological variables and clinical outcome., Results: We observed that the methylation of diverse CpG islands of TP73 differed significantly between molecular subtypes. An inverse correlation was found between p73 protein expression and the methylation status of the TP73 gene. The expression of exon 3' of p73 (only expressed in ΔNp73) was significantly higher in patients with wild-type p53. Immunohistochemical analysis revealed that all p73 isoforms were localised in both the nuclear and cytoplasmic compartments. We confirmed a positive association between the expression of ∆Np73 and high histological grade., Conclusions: Our findings suggest that high expression of ΔNp73 could be used to determine the aggressiveness of IDCs and could be incorporated in the pathologist's report., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
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- 2018
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5. HER2 and β-catenin protein location: importance in the prognosis of breast cancer patients and their correlation when breast cancer cells suffer stressful situations.
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Cuello-Carrión FD, Shortrede JE, Alvarez-Olmedo D, Cayado-Gutiérrez N, Castro GN, Zoppino FC, Guerrero M, Martinis E, Wuilloud R, Gómez NN, Biaggio V, Orozco J, Gago FE, Ciocca LA, Fanelli MA, and Ciocca DR
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- Antineoplastic Agents pharmacology, Apoptosis, Breast Neoplasms mortality, Cadmium pharmacology, Cell Line, Tumor, Cell Membrane metabolism, Cytoplasm metabolism, Dose-Response Relationship, Drug, Female, Humans, Hydrogen Peroxide chemistry, Immunohistochemistry, Prognosis, Tamoxifen pharmacology, Treatment Outcome, Breast Neoplasms diagnosis, Breast Neoplasms metabolism, Receptor, ErbB-2 metabolism, beta Catenin metabolism
- Abstract
In human breast cancer, β-catenin localization has been related with disease prognosis. Since HER2-positive patients are an important subgroup, and that in breast cancer cells a direct interaction of β-catenin/HER2 has been reported, in the present study we have explored whether β-catenin location is related with the disease survival. The study was performed in a tumor bank from patients (n = 140) that did not receive specific anti-HER2 therapy. The proteins were detected by immunohistochemistry in serial sections, 47 (33.5%) patients were HER2-positive with a long follow-up. HER2-positive patients that displayed β-catenin at the plasma membrane (completely surrounding the tumour cells) showed a significant better disease-free survival and overall survival than the patients showing the protein on other locations. Then we explored the dynamics of the co-expression of β-catenin and HER2 in human MCF-7 and SKBR3 cells exposed to different stressful situations. In untreated conditions MCF-7 and SKBR3 cells showed very different β-catenin localization. In MCF-7 cells, cadmium administration caused a striking change in β-catenin localization driving it from plasma membrane to cytoplasmic and perinuclear areas and HER2 showed a similar localization patterns. The changes induced by cadmium were compared with heat shock, H2O2 and tamoxifen treatments. In conclusion, this study shows the dynamical associations of HER2 and β-catenin and their changes in subcellular localizations driven by stressful situations. In addition, we report for the first time the correlation between plasma membrane associated β-catenin in HER2-positive breast cancer and survival outcome, and the importance of the protein localization in breast cancer samples.
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- 2015
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6. Prognostic implication of HSPA (HSP70) in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy.
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Nadin SB, Sottile ML, Montt-Guevara MM, Gauna GV, Daguerre P, Leuzzi M, Gago FE, Ibarra J, Cuello-Carrión FD, Ciocca DR, and Vargas-Roig LM
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- Adult, Aged, Breast drug effects, Breast Neoplasms pathology, Doxorubicin therapeutic use, Epirubicin therapeutic use, Female, Follow-Up Studies, HSP27 Heat-Shock Proteins analysis, Humans, Immunohistochemistry, Middle Aged, Prognosis, Anthracyclines therapeutic use, Antibiotics, Antineoplastic therapeutic use, Breast pathology, Breast Neoplasms diagnosis, Breast Neoplasms drug therapy, HSP70 Heat-Shock Proteins analysis, Neoadjuvant Therapy
- Abstract
Neoadjuvant chemotherapy is used in patients with locally advanced breast cancer to reduce tumor size before surgery. Unfortunately, resistance to chemotherapy may arise from a variety of mechanisms. Heat shock proteins (HSPs), which are highly expressed in mammary tumor cells, have been implicated in anticancer drug resistance. In spite of the widely described value of HSPs as molecular markers in cancer, their implications in breast tumors treated with anthracycline-based neoadjuvant chemotherapy has been poorly explored. In this study, we have evaluated, by immunohistochemistry, the expression of HSP27 (HSPB1) and HSP70 (HSPA) in serial biopsies from locally advanced breast cancer patients (n = 60) treated with doxorubicin (DOX)- or epirubicin (EPI)-based monochemotherapy. Serial biopsies were taken at days 1, 3, 7, and 21, and compared with prechemotherapy and surgical biopsies. After surgery, the patients received additional chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil. High nuclear HSPB1 and HSPA expressions were found in invasive cells after DOX/EPI administration (P < 0.001), but the drug did not affect the cytoplasmic expression of the HSPs. Infiltrating lymphocytes showed high nuclear HSPA (P < 0.01) levels at postchemotherapy. No correlations were found between HSPs expression and the clinical and pathological response to neoadjuvant therapy. However, in postchemotherapy biopsies, high nuclear (>31 % of the cells) and cytoplasmic HSPA expressions (>11 % of the tumor cells) were associated with better DFS (P = 0.0348 and P = 0.0118, respectively). We conclude that HSPA expression may be a useful prognostic marker in breast cancer patients treated with neoadjuvant DOX/EPI chemotherapy indicating the need to change the administered drugs after surgery for overcoming drug resistance.
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- 2014
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7. In MMTV-Her-2/neu transgenic mammary tumors the absence of caveolin-1-/- alters PTEN and NHERF1 but not β-catenin expression.
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Cuello-Carrión FD, Cayado-Gutiérrez N, Natoli AL, Restall C, Anderson RL, Nadin S, Alvarez-Olmedo D, Castro GN, Gago FE, Fanelli MA, and Ciocca DR
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- Animals, Caveolin 1 genetics, Female, Humans, Immunohistochemistry, MCF-7 Cells, Mammary Neoplasms, Animal pathology, Mice, Mice, Knockout, Mice, Transgenic, Proto-Oncogene Proteins c-akt metabolism, Receptor, ErbB-2 genetics, beta Catenin genetics, Caveolin 1 metabolism, Mammary Neoplasms, Animal metabolism, Mammary Tumor Virus, Mouse genetics, PTEN Phosphohydrolase metabolism, Phosphoproteins metabolism, Receptor, ErbB-2 metabolism, Sodium-Hydrogen Exchangers metabolism, beta Catenin metabolism
- Abstract
In a recent study, we have shown that in mammary tumors from mice lacking the Cav-1 gene, there are alterations in specific heat shock proteins as well as in tumor development. With this in mind, we have now investigated other proteins in the same mammary mouse tumor model (Her-2/neu expressing mammary tumors from Cav-1 wild type and Cav-1 null mice), to further comprehend the complex tumor-stroma mechanisms involved in regulating stress responses during tumor development. In this tumor model the cancer cells always lacked of Cav-1, so the KO influenced the Cav-1 in the stroma. By immunohistochemistry, we have found a striking co-expression of β-catenin and Her-2/neu in the tumor cells. The absence of Cav-1 in the tumor stroma had no effect on expression or localization of β-catenin and Her-2/neu. Both proteins appeared co-localized at the cell surface during tumor development and progression. Since Her-2/neu activation induces MTA1, we next evaluated MTA1 in the mouse tumors. Although this protein was found in numerous nuclei, the absence of Cav-1 did not alter its expression level. In contrast, significantly more PTEN protein was noted in the tumors lacking Cav-1 in the stroma, with the protein localized mainly in the nuclei. P-Akt levels were relatively low in tumors from both Cav-1 WT and Cav-1 KO mice. There was also an increase in nuclear NHERF1 expression levels in the tumors arising from Cav-1 KO mice. The data obtained in the MMTV-neu model are consistent with a role for Cav-1 in adjacent breast cancer stromal cells in modulating the expression and localization of important proteins implicated in tumor cell behavior.
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- 2013
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8. DNA methylation index and methylation profile of invasive ductal breast tumors.
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Marzese DM, Hoon DS, Chong KK, Gago FE, Orozco JI, Tello OM, Vargas-Roig LM, and Roqué M
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- Adult, Breast metabolism, Breast pathology, Breast Neoplasms diagnosis, Breast Neoplasms pathology, Carcinoma, Ductal, Breast diagnosis, Carcinoma, Ductal, Breast pathology, Cluster Analysis, DNA-Binding Proteins genetics, Female, Humans, Middle Aged, Nuclear Proteins genetics, Prognosis, Receptors, Retinoic Acid genetics, Tumor Protein p73, Tumor Suppressor Proteins genetics, WT1 Proteins genetics, Breast Neoplasms genetics, Carcinoma, Ductal, Breast genetics, CpG Islands, DNA Methylation, Gene Expression Regulation, Neoplastic
- Abstract
Breast carcinogenesis is a multistep process that involves both genetic and epigenetic alterations. Identification of aberrantly methylated genes in breast tumors and their relation to clinical parameters can contribute to improved diagnostic, prognostic, and therapeutic decision making. Our objective in the present study was to identify the methylation status of 34 cancer-involved genes in invasive ductal carcinomas (IDC). Each of the 70 IDC cases analyzed had a unique methylation profile. The highest methylation frequency was detected in the WT1 (95.7%) and RASSF1 (71.4%) genes. Hierarchical cluster analysis revealed three clusters with different distribution of the prognostic factors tumor grade, lymph node metastasis, and proliferation rate. Methylation of TP73 was associated with high histological grade and high proliferation rate; methylation of RARB was associated with lymph node metastasis. Concurrent methylation of TP73 and RARB was associated with high histological grade, high proliferation rate, increased tumor size, and lymph node metastasis. Patients with more than six methylated genes had higher rates of relapse events and cancer deaths. In multivariate analysis, TP73 methylation and the methylation index were associated with disease outcome. Our results indicate that methylation index and methylation of TP73 and/or RARB are related to unfavorable prognostic factors in patients with IDC. These epigenetic markers should be validated in further studies to improve breast cancer management., (Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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9. Methylation profile of triple-negative breast carcinomas.
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Branham MT, Marzese DM, Laurito SR, Gago FE, Orozco JI, Tello OM, Vargas-Roig LM, and Roqué M
- Abstract
Breast cancer is a group of clinically, histopathologically and molecularly heterogeneous diseases, with different outcomes and responses to treatment. Triple-negative (TN) breast cancers are defined as tumors that lack the expression of estrogen receptor, progesterone receptor and epidermal growth factor receptor 2. This subgroup accounts for 15% of all types of breast cancer and its prevalence is higher among young African, African-American and Latino women. The hypermethylation of CpG islands (CpGI) is a common epigenetic alteration for suppressing gene expression in breast cancer and has been shown to be a key factor in breast carcinogenesis. In this study we analyzed the hypermethylation of 110 CpGI within 69 cancer-related genes in TN tumors. For the methylation analysis, we used the methyl-specific multiplex-ligation probe amplification assay. We found that the number of methylated CpGI is similar between TN and non-TN tumors, but the methylated genes between the groups are different. The methylation profile of TN tumors is defined by the methylation of five genes (that is, CDKN2B, CD44, MGMT, RB and p73) plus the non-methylation of 11 genes (that is, GSTP1, PMS2, MSH2, MLH1, MSH3, MSH6, DLC1, CACNA1A, CACNA1G, TWIST1 and ID4). We conclude that TN tumors have a specific methylation profile. Our findings give new information for better understanding tumor etiology and encourage future studies on potential drug targets for triple-negative breast tumors, which now lack a specific treatment.
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- 2012
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10. Aberrant DNA methylation of cancer-related genes in giant breast fibroadenoma: a case report.
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Marzese DM, Gago FE, Orozco JI, Tello OM, Roqué M, and Vargas-Roig LM
- Abstract
Introduction: Giant fibroadenoma is an uncommon variant of benign breast lesions. Aberrant methylation of CpG islands in promoter regions is known to be involved in the silencing of genes (for example, tumor-suppressor genes) and appears to be an early event in the etiology of breast carcinogenesis. Only hypermethylation of p16INK4a has been reported in non-giant breast fibroadenoma. In this particular case, there are no previously published data on epigenetic alterations in giant fibroadenomas. Our previous results, based on the analysis of 49 cancer-related CpG islands have confirmed that the aberrant methylation is specific to malignant breast tumors and that it is completely absent in normal breast tissue and breast fibroadenomas., Case Presentation: A 13-year-old Hispanic girl was referred after she had noted a progressive development of a mass in her left breast. On physical examination, a 10 × 10 cm lump was detected and axillary lymph nodes were not enlarged. After surgical removal the lump was diagnosed as a giant fibroadenoma. Because of the high growth rate of this benign tumor, we decided to analyze the methylation status of 49 CpG islands related to cell growth control. We have identified the methylation of five cancer-related CpG islands in the giant fibroadenoma tissue: ESR1, MGMT, WT-1, BRCA2 and CD44., Conclusion: In this case report we show for the first time the methylation analysis of a giant fibroadenoma. The detection of methylation of these five cancer-related regions indicates substantial epigenomic differences with non-giant fibroadenomas. Epigenetic alterations could explain the higher growth rate of this tumor. Our data contribute to the growing knowledge of aberrant methylation in breast diseases. In this particular case, there exist no previous data regarding the role of methylation in giant fibroadenomas, considered by definition as a benign breast lesion.
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- 2011
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11. Simultaneous analysis of the methylation profile of 26 cancer related regions in invasive breast carcinomas by MS-MLPA and drMS-MLPA.
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Marzese DM, Gago FE, Vargas-Roig LM, and Roqué M
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- Breast Neoplasms blood, Breast Neoplasms pathology, Cell Line, Tumor, DNA Probes, DNA, Neoplasm blood, DNA, Neoplasm genetics, Female, HeLa Cells, Humans, Neoplasm Invasiveness, Polymerase Chain Reaction methods, Reproducibility of Results, Breast Neoplasms genetics, DNA Methylation, Genetic Predisposition to Disease genetics, Nucleic Acid Amplification Techniques methods
- Abstract
Genetic and epigenetic events play a critical role in the tumorigenic process of breast cancer. The more genes are studied, the more accurate the epigenetic "signature" can be established. The aim of our work has been to apply the technique Methylation-Specific Multiplex Ligation dependent Probe Amplification (MS-MLPA) to study the methylation profile of 26 cancer related gene regions in breast cancers. Secondly, we aimed to establish if the epigenetic "signature" could serve to detect circulating tumor DNA (ctDNA) in breast cancer patients. The MS-MLPA was successfully setup and allowed to establish which regions were preferentially associated with the tumor process. The analysis permitted also to detect significant concurrent methylation between some genes. The detection of ctDNA could be performed by a "double-round" MS-MLPA (drMS-MLPA) approach and nested-Methyl Specific PCR (Nested-MSP). This development is an important novelty and served to detect a small amount of tumor DNA shaded into the blood stream of breast cancer patients. We conclude that MS-MLPA is an excellent assay to analyze the methylation profile of a tumor. The 82 studied samples presented a specific methylation "mark". These studies serve to enhance the knowledge of the role of epigenetic alterations in breast tumors and can contribute to the development of personalized diagnosis, surveillance and treatment strategies., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)
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- 2010
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12. Stromal cell expression of caveolin-1 predicts outcome in breast cancer.
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Sloan EK, Ciocca DR, Pouliot N, Natoli A, Restall C, Henderson MA, Fanelli MA, Cuello-Carrión FD, Gago FE, and Anderson RL
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- Adult, Aged, Aged, 80 and over, Animals, Breast Neoplasms genetics, Breast Neoplasms pathology, Caveolin 1 genetics, Female, Humans, Kaplan-Meier Estimate, Mice, Mice, Knockout, Mice, Transgenic, Middle Aged, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Neoplasm Staging, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptors, Estrogen biosynthesis, Receptors, Progesterone biosynthesis, Receptors, Virus genetics, Receptors, Virus metabolism, Treatment Outcome, Biomarkers, Tumor analysis, Breast Neoplasms metabolism, Caveolin 1 biosynthesis, Stromal Cells metabolism
- Abstract
Caveolin-1 has been linked to tumor progression and clinical outcome in breast cancer, but a clear resolution of its role as a prognostic marker is lacking. We assessed caveolin-1 levels in normal breast tissue and two breast cancer cohorts for which outcome data were available. We found that caveolin-1 was not expressed in normal breast luminal epithelium but was present in the epithelial compartment of some tumors. We found no association between caveolin-1 expression in the epithelial compartment and clinical outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor, rather than within tumor cells, associated strongly with reduced metastasis and improved survival (P < 0.0001). The onset of mammary tumors driven by Her2/neu overexpression was accelerated in mice lacking caveolin-1, thereby supporting the observation that the presence of caveolin-1 in the tumor microenvironment modulates tumor development. These studies suggest that stromal caveolin-1 expression may be a potential therapeutic target and a valuable prognostic indicator of breast cancer progression.
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- 2009
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13. Prognostic value of Bcl-2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.
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Vargas-Roig LM, Cuello-Carrión FD, Fernández-Escobar N, Daguerre P, Leuzzi M, Ibarra J, Gago FE, Nadin SB, and Ciocca DR
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- Anthracyclines therapeutic use, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms drug therapy, Female, Humans, Neoadjuvant Therapy methods, Prognosis, Survival Analysis, Treatment Outcome, bcl-2-Associated X Protein analysis, Antibiotics, Antineoplastic therapeutic use, Breast Neoplasms diagnosis, Breast Neoplasms mortality, Predictive Value of Tests, Proto-Oncogene Proteins c-bcl-2 analysis
- Abstract
We have analyzed the predictive/prognostic value of Bcl-2 protein in breast cancer patients treated with neoadjuvant chemotherapy. One hundred and ten patients were submitted to two different chemotherapeutic regimens: a) 5-fluorouracil, adriamycin or epirubicin, and cyclophosphamide (FAC/FEC) during 2-6 cycles before surgery and 3 or 4 additional cycles of FAC/FEC after surgery (n=40) and b) doxorubicin (D) 75 mg/m(2) or epirubicin (E) 120 mg/m(2) during 4 cycles before surgery, and 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) after surgery (n=70). Bcl-2 expression, evaluated by immunohistochemistry, did not change significantly after chemotherapy and was not related to clinical/pathological response. In FAC/FEC group, Bcl-2 positive expression after chemotherapy correlated with better disease free survival (DFS) and overall survival (OS) (P=0.008 and P=0.001). In D/E group, Bcl-2 also correlated with better DFS and OS (P=0.03 and P=0.054) in the post-chemotherapy biopsies. An unusual nuclear localization of Bax was observed in some biopsies, but this localization did not correlate with the tumor response or outcome of the patients. We found that a high Bcl-2 expression had no predictive value but had prognostic value in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.
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- 2008
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14. P-cadherin and beta-catenin are useful prognostic markers in breast cancer patients; beta-catenin interacts with heat shock protein Hsp27.
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Fanelli MA, Montt-Guevara M, Diblasi AM, Gago FE, Tello O, Cuello-Carrión FD, Callegari E, Bausero MA, and Ciocca DR
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- Adult, Aged, Aged, 80 and over, Animals, Biopsy, Breast Neoplasms mortality, Breast Neoplasms pathology, Carcinoma mortality, Carcinoma pathology, Cell Line, Tumor metabolism, Disease-Free Survival, Female, HSP27 Heat-Shock Proteins metabolism, Heat-Shock Proteins, Humans, Kaplan-Meier Estimate, Mammary Neoplasms, Experimental pathology, Mice, Middle Aged, Molecular Chaperones, Neoplasm Proteins metabolism, Prognosis, Protein Interaction Mapping, Receptor, ErbB-2 analysis, beta Catenin metabolism, Breast Neoplasms chemistry, Cadherins analysis, Carcinoma chemistry, HSP27 Heat-Shock Proteins analysis, Neoplasm Proteins analysis, beta Catenin analysis
- Abstract
The cadherin-catenin proteins have in common with heat shock proteins (HSP) the capacity to bind/interact proteins of other classes. Moreover, there are common molecular pathways that connect the HSP response and the cadherin-catenin protein system. In the present study, we have explored whether in breast cancer the HSP might interact functionally with the cadherin-catenin cell adhesion system. Beta-catenin was immunoprecipitated from breast cancer biopsy samples, and the protein complexes isolated in this way were probed with antibodies against HSP family members. We are thus the first to demonstrate a specific interaction between beta-catenin and Hsp27. However, beta-catenin did not bind Hsp60, Hsp70, Hsp90, gp96, or the endoplasmic reticulum stress response protein CHOP. To confirm the finding of Hsp27-beta-catenin interaction, the 27-kDa immunoprecipitated band was excised from one-dimensional polyacrylamide gel electrophoresis gels and submitted to liquid chromatography-tandem mass spectrometry with electrospray ionization, confirming a role for Hsp27. In addition, beta-catenin interacted with other proteins including heat shock transcription factor 1, P-cadherin, and caveolin-1. In human breast cancer biopsy samples, beta-catenin was coexpressed in the same tumor areas and in the same tumor cells that expressed Hsp27. However, this coexpression was strong when beta-catenin was present in the cytoplasm of the tumor cells and not when beta-catenin was expressed at the cell surface only. Furthermore, murine breast cancer cells transfected with hsp25 showed a redistribution of beta-catenin from the cell membrane to the cytoplasm. When the prognostic significance of cadherin-catenin expression was examined by immunohistochemistry in breast cancer patients (n = 215, follow-up = >10 years), we found that the disease-free survival and overall survival were significantly shorter for patients expressing P-cadherin and for patients showing expression of beta-catenin in the cytoplasm only (not at the cell surface). The interactions of beta-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients.
- Published
- 2008
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15. Co-expression of steroid receptors (estrogen receptor alpha and/or progesterone receptors) and Her-2/neu: Clinical implications.
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Ciocca DR, Gago FE, Fanelli MA, and Calderwood SK
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- Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Gene Expression Regulation, Neoplastic, Humans, Tamoxifen therapeutic use, Breast Neoplasms metabolism, Estrogen Receptor alpha metabolism, Receptor, ErbB-2 metabolism, Receptors, Progesterone metabolism
- Abstract
The response of breast cancer patients to endocrine therapy is guided by the expression of two steroid hormone receptors (HR): estrogen receptor alpha (ERalpha) and/or progesterone receptors (PR). In most laboratories the expression of these predictive markers is studied by immunohistochemistry (IHC) in the breast cancer biopsy samples. Another molecular marker that is being increasingly examined in breast cancer is the oncoprotein Her-2/neu, whose expression/amplification predicts the response to anti-Her-2/neu immunotherapy. The co-expression of HR with that of Her-2/neu is infrequent (most reports agree on this), however, there are some conflicting reports about the clinical implications in term of response to endocrine therapy in the patients that co-express HR and Her-2/neu. We have examined these molecular markers for a number of years in our tumor bank, in this dissertation we will present the method and cut-off to study these markers, the correlations between their expression, and the follow-up of the patients that received tamoxifen-based endocrine therapy, alone or following chemotherapy. We confirmed that the co-expression of HR with Her-2/neu is infrequent, and that these patients presented both a shorter disease free survival and overall survival. Our results will be compared with others related recently published. For example, the aromatase inhibitor anastrozole appears to be an effective endocrine treatment in HR+ patients, irrespective of the Her-2/neu status. We will present data on the molecular mechanisms that could explain the relatively poor outcome of these patients. Heregulin has been found to be a potent inducer of heat shock factor 1 (HSF1) activity and of heat shock protein (Hsp) synthesis in breast cancer cells and HSF1 activation plays a role in the tumorigenic changes induced by heregulin, heregulin exerts its tumorigenic changes through the cell surface tyrosine kinase receptors c-erbB-3 and c-erbB-4 which are able to form dimers with the "ligandless" Her-2/neu. We found that HSF1 associates with metastasis associated protein 1 (MTA1) on the promoters of genes as well as other molecules involved in gene repression (HDAC1, HDAC2) in a manner that is enhanced by either heregulin exposure or heat shock. ERs, although promoting the growth of breast cancer cells are less associated with invasion/metastasis and ER-induced gene expression is involve in this effect. Heregulin can overcome the protective effects of ER and at least a component of this appears to be due to MTA1 repression of ERE dependent transcription, HSF1 and MTA1 cooperate in gene repression. The co-expression of HSF1 and MTA1 was confirmed by IHC in human breast cancer biopsy samples.
- Published
- 2006
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16. Co-expression of steroid hormone receptors (estrogen receptor alpha and/or progesterone receptors) and Her2/neu (c-erbB-2) in breast cancer: clinical outcome following tamoxifen-based adjuvant therapy.
- Author
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Gago FE, Fanelli MA, and Ciocca DR
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- Adult, Aged, Aged, 80 and over, Breast Neoplasms pathology, Chemotherapy, Adjuvant, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Prospective Studies, Survival Rate, Treatment Outcome, Tumor Cells, Cultured, Antineoplastic Agents, Hormonal therapeutic use, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Estrogen Receptor alpha metabolism, Receptor, ErbB-2 metabolism, Receptors, Progesterone metabolism, Tamoxifen therapeutic use
- Abstract
In breast cancer patients, the expression of steroid hormone receptors (HR:ERalpha/PR) appears inversely correlated with Her2/neu (not all reports agree on this negative correlation). Moreover, some but not all studies suggest that HR+/Her2/neu+ patients have a poor response to endocrine therapy, making this special group a matter of debate. In this prospective study we have analyzed the clinical outcome of our HR+/Her2/neu+ patients (n=51) selected from 516 consecutive stages I-II cases, with a follow-up 5-10 years (mean 7.3), treated with standard adjuvant therapy with tamoxifen (TAM) (TAM alone or TAM after chemotherapy). This group was compared with the HR+/Her-2/neu- patients (n=129) treated also with TAM. The tumor biopsies were studied by immunohistochemistry. We found that the association HR+/Her2/neu- was 2.5 times higher than the association HR+/Her2/neu+ (25% versus 9.9%, respectively). Our study also showed that the disease free survival (DFS) of the patients co-expressing HR and Her2/neu was significantly lower than those expressing HR but lacking of Her2/neu (p<0.001). A similar result was obtained when the overall survival (OS) was evaluated (p=0.001). All of these patients received hormone therapy with TAM, alone or after chemotherapy. When the analysis was performed in the patients treated with TAM alone, again the expression of Her-2/neu had a negative impact on both the DFS and the OS (p<0.05).
- Published
- 2006
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17. c-erbB-2 (HER-2/neu) protein and drug resistance in breast cancer patients treated with induction chemotherapy.
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Vargas-Roig LM, Gago FE, Tello O, Martin de Civetta MT, and Ciocca DR
- Subjects
- Adult, Aged, Breast Neoplasms drug therapy, Cyclophosphamide administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Drug Resistance, Neoplasm, Epirubicin administration & dosage, Female, Fluorouracil administration & dosage, Humans, Middle Aged, Prospective Studies, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms metabolism, Receptor, ErbB-2 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Expression of c-erbB-2 protein has been associated with poor prognosis and poor response to chemotherapy in breast cancer patients. In the present prospective study, we have analyzed whether c-erbB-2, p53 and P170 proteins may be determinants of tumor resistance in locally advanced breast cancer patients treated with induction chemotherapy. Biopsies (n = 60) were examined by immuno-histochemistry; in 62% of cases core or incisional biopsies were taken before drug administration, allowing comparison in paired biopsies of the cytological and molecular changes induced by treatment Sixty percent of the patients received relatively high doses of FAC or FEC (5-fluorouracil, doxorubicin or epirubicin and cyclophosphamide), and 40% received relatively high doses of doxorubicin or epirubicin alone. No significant changes were observed in the molecular markers studied following chemotherapy; in the few biopsies where changes appeared, the changes did not exhibit any significant or similar trend. For 30 of the patients who received FAC/FEC treatment, follow-up reached a median of 34 months. In these cases, neither the clinical (reduction in tumor size) nor the histological (evaluated after neoadjuvant chemotherapy) responses showed statistically significant differences between the patients who developed distant metastases and the disease-free patients. c-erbB-2 was over-expressed in 50% of patients who developed distant metastases vs. 7% of the disease-free patients. Disease free survival (DFS) curves between c-erbB-2-positive and c-erbB-2-negative patients were statistically significant. No correlation between p53 or P170 expression with DFS was found. Our results suggest that c-erbB-2 protein expression is associated with development of distant metastases in breast cancer patients treated with relatively high doses of anthracyclines in induction chemotherapy.
- Published
- 1999
- Full Text
- View/download PDF
18. Integration of estrogen and progesterone receptors with pathological and molecular prognostic factors in breast cancer patients.
- Author
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Gago FE, Tello OM, Diblasi AM, and Ciocca DR
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 analysis, Analysis of Variance, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biopsy, Breast Neoplasms chemistry, Breast Neoplasms surgery, Breast Neoplasms therapy, Chemotherapy, Adjuvant, Combined Modality Therapy, Disease-Free Survival, Female, Follow-Up Studies, Humans, Lymphatic Metastasis, Middle Aged, Multivariate Analysis, Neoplasm Metastasis, Probability, Prognosis, Proliferating Cell Nuclear Antigen analysis, Receptor, ErbB-2 analysis, Survival Rate, Tamoxifen therapeutic use, Time Factors, Tumor Suppressor Protein p53 analysis, Breast Neoplasms pathology, Receptors, Estrogen analysis, Receptors, Progesterone analysis
- Abstract
In this study we have examined biopsies from women with localized primary breast cancer to investigate the prognostic performance of estrogen receptors (ER) and progesterone receptors (PR) for estimating the metastatic probability of the patients, and to explore whether discrimination gets better by combining clinicopathological and other molecular parameters into a score. This prospective study involved 205 patients with a median follow-up of 5 y. Among the evaluated clinicopathological data were: patient's age; tumor size; axillary lymph node involvement; and tumor grade. The most representative tumor samples were derived to a single laboratory for immunohistochemical evaluation of the following molecular markers: ER, PR, proliferating cell nuclear antigen (PCNA), p53 protein product, erbB-2 (HER-2/neu) oncoprotein, and P170 glycoprotein (mdrl gen product). Distant metastases (study endpoint) appeared in 19.5% (40/205) of the patients, most of these patients presented a mixture of poor, regular and good prognostic factors. Disease-free survival analysis procedures (Kaplan-Meier method) identified tumor size, axillary lymph node involvement, tumor grade, receptor status, PCNA, p53, erbB-2 and P170 as useful prognostic factors. Proportional hazard regression analysis (Cox) identified in order of importance erbB-2, tumor size, receptors status, tumor grade and PCNA as useful prognostic factors. To facilitate the evaluation of the prognostic factors, a practical and simple score system was derived. A high pathological score identified 65% of the patients that developed distant metastases, while a high molecular score was obtained in 57% of patients with metastatic disease. There was a significant improvement in the diagnosis of probability of being with distant metastases when the pathological score was combined with the molecular score, 82% of the patients with distant metastases showed an elevated combined score. Validation of this scoring system will need further larger studies (validation set as opposed to the training set used in the present study). Due to the complexity of events in cancer, the evaluation of a combination of prognostic factors should be of value to clinicians to make a more objective estimate of the prognosis of individual breast cancer patients.
- Published
- 1998
- Full Text
- View/download PDF
19. Heat shock protein expression and drug resistance in breast cancer patients treated with induction chemotherapy.
- Author
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Vargas-Roig LM, Gago FE, Tello O, Aznar JC, and Ciocca DR
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Biopsy, Breast Neoplasms pathology, Cell Division, Cisplatin administration & dosage, Cyclophosphamide administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Epirubicin administration & dosage, Fluorouracil administration & dosage, HSP70 Heat-Shock Proteins analysis, Humans, Methotrexate administration & dosage, Middle Aged, Nucleolus Organizer Region pathology, Prognosis, Proliferating Cell Nuclear Antigen analysis, Silver Staining, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Breast Neoplasms chemistry, Breast Neoplasms drug therapy, Drug Resistance, Neoplasm, Heat-Shock Proteins analysis
- Abstract
Heat shock proteins (Hsps) are induced in vitro by several cytotoxic drugs; in human breast cancer cells these proteins appear to be involved in anti-cancer drug resistance. The present report was designed to analyze whether chemotherapy affects in vivo the expression of Hsp27, Hsp70, Hsc70 and Hsp90 in breast cancer patients treated with induction chemotherapy and whether these proteins may be determinants of tumor resistance to drug administration. We have analyzed 35 biopsies from breast cancer patients treated with induction chemotherapy. Expression of the Hsps in the tumors was compared with (i) histological and clinical responses to chemotherapy, (ii) tumor cell proliferation measured by proliferating cell nuclear antigen (PCNA) immunostaining and nucleolar organizer regions (AgNORs) staining and (iii) the expression of estrogen and progesterone receptors. We also compared disease-free survival (DFS) and overall survival (OS) with the expression of the Hsps studied. After chemotherapy, nuclear Hsp27 and Hsp70 expression was increased and Hsp70 and Hsc70 cytoplasmic expression was decreased. A high nuclear proportion of Hsp70 in tumor cells (>10%) correlated significantly with drug resistance. We also observed that patients whose tumors expressed nuclear or a high cytoplasmic proportion (>66%) of Hsp27 had shorter DFS. The combination of Hsp27 and Hsp70 levels showed a strong correlation with DFS. Neither the cellular proliferation nor the levels of steroid receptors showed any significant difference before or after drug administration or during follow-up of patients. Our results suggest that Hsp27 and Hsp70 are involved in drug resistance in breast cancer patients treated with combination chemotherapies.
- Published
- 1998
- Full Text
- View/download PDF
20. Heat shock proteins and cell proliferation in human breast cancer biopsy samples.
- Author
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Vargas-Roig LM, Fanelli MA, López LA, Gago FE, Tello O, Aznar JC, and Ciocca DR
- Subjects
- Adult, Aged, Biopsy, Blotting, Western, Cell Division physiology, Female, Humans, Middle Aged, Nucleolus Organizer Region, Proliferating Cell Nuclear Antigen analysis, Silver Staining, Breast Neoplasms metabolism, Breast Neoplasms pathology, HSP70 Heat-Shock Proteins metabolism, Heat-Shock Proteins metabolism, Neoplasm Proteins metabolism
- Abstract
Human breast cancers may overexpress certain heat shock protein (hsp) family members, proteins which are involved with cell proliferation and differentiation as well as with disease prognosis and drug resistance. Here, we have studied the relationship between the expression of two hsps (hsp27 and hsp70) and the proliferative activity of tumor cells in 40 biopsies from breast cancer patients. Twenty of these tumors were selected for a detailed colocalization study. Immunocytochemistry was done using specific antibodies against hsp27 and hsp70. Cell proliferation was studied analyzing the expression of proliferating cell nuclear antigen (PCNA) (late G1, S, and G2 phases of the cell cycle) and the number of silver-staining nucleolar organizer regions (AgNORs) (G1 phase). The colocalization study revealed a statistically significant inverse correlation between hsp27 expression and cell proliferation in 16/19 (84%) of the cases evaluated by PCNA immunostaining, and in 11/16 (69%) of the cases evaluated by AgNORs. In contrast, a statistically significant positive correlation between hsp70 expression and elevated cell proliferation was seen in almost 85% of the cases evaluated by PCNA staining, and in almost 50% of the cases evaluated by AgNORs. Moreover, in 22% (9/40) of the breast cancer samples examined, hsp70 was clearly associated with the mitotic spindle. A Western blot analysis revealed that hsp70 was coprecipitated with taxol-polymerized tubulin. The association of hsp70 with the mitotic spindle was not clearly noted in lung carcinoma samples (N = 20) or in normal cells displaying elevated mitotic activity. These studies thus demonstrate that in a significant percentage of clinical breast cancers hsp27 overexpression is inversely correlated with cell proliferation, while hsp70 is clearly associated with the mitotic spindle and cell proliferation. These results add evidence to the concept that in human breast cancers hsp27 may be involved in cell growth arrest and increased differentiation while, in contrast, hsp70 may be involved in cell proliferation; further studies will be necessary to elucidate these possible cause-and-effect relationships.
- Published
- 1997
21. Estrogen receptors, progesterone receptors, and cell proliferation in human breast cancer.
- Author
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Fanelli MA, Vargas-Roig LM, Gago FE, Tello O, Lucero De Angelis R, and Ciocca DR
- Subjects
- Adult, Aged, Aged, 80 and over, Breast Neoplasms pathology, Cell Division, Female, Humans, Middle Aged, Nucleolus Organizer Region, Proliferating Cell Nuclear Antigen analysis, Breast Neoplasms chemistry, Receptors, Estrogen analysis, Receptors, Progesterone analysis
- Abstract
The breast is a target organ for estrogens and progesterone. These hormones control several functions of the normal and abnormal mammary epithelium including cell proliferation. Most of the actions of estrogens and progesterone are mediated via specific steroid receptors, and one would expect that proliferating cells should contain estrogen receptors (ER) and/or progesterone receptors (PR). However, the correlation between receptor expression and cell proliferation is still controversial. In the present study we have examined 29 human breast cancer samples; in 17 of them we evaluated the simultaneous ER and PR localization with that of proliferating cell nuclear antigen (PCNA) and silver-stained nucleolar organizer regions (AgNORs) in a cell-by-cell study. We found that in almost 50% of the tumor biopsies examined, the cells expressing ER were significantly associated with elevated cell proliferation. In another group (38%) there were not significant differences between ER expression and cell proliferation. In only one of the samples (6%) the cells expressing ER showed lower cell proliferation. The study also revealed that in 44% of the tumors the PR expressing cells were associated with elevated cell proliferation. In a second group the PR expression was not significantly associated with cell proliferation (33% of the cases). Finally, in 22% of the samples the cells carrying PR showed lower cell proliferation. We also detected lower ER immunoreactivity in 30% of the breast cancer biopsies with one of the monoclonal antibodies against ER (antibody 1D5 directed against the A/B domain). This group of tumors was PR-negative (or very weakly positive) and had high proliferation. The presence of tumors with 'abnormal' ER proteins and displaying ER/PR significantly associated with elevated cell proliferation could have implications in human breast cancer treatment.
- Published
- 1996
- Full Text
- View/download PDF
22. Corticotropin-releasing hormone, luteinizing hormone-releasing hormone, growth hormone-releasing hormone, and somatostatin-like immunoreactivities in biopsies from breast cancer patients.
- Author
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Ciocca DR, Puy LA, Fasoli LC, Tello O, Aznar JC, Gago FE, Papa SI, and Sonego R
- Subjects
- Biopsy, Breast Neoplasms pathology, Carcinoma pathology, Humans, Breast Neoplasms analysis, Carcinoma analysis, Corticotropin-Releasing Hormone analysis, Gonadotropin-Releasing Hormone analysis, Growth Hormone-Releasing Hormone analysis, Peptides analysis, Somatostatin analysis
- Abstract
The presence of immunoreactive adrenocorticotropin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LHRH), growth hormone-releasing hormone (GHRH), and somatostatin has been investigated by immunohistochemistry in forty biopsies from breast cancer patients. All of these hypothalamic hormones were found in about 30% of the samples, seen in the cytoplasm or in the nuclei of the tumor cells. Positive immunostaining for the hypothalamic hormones was present in colloid, lobular, and infiltrating ductal carcinomas. There was not a clear relationship between occurrence of staining for the hypothalamic hormones and the histologic grade of tumors or the clinical stage of the disease. Immunoreactive LHRH was more frequently found in breast tumors with estrogen and progesterone receptors. On the other hand, preneoplastic breast lesions expressed mainly somatostatin, while immunoreactivity was absent in normal mammary tissue.
- Published
- 1990
- Full Text
- View/download PDF
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