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Autoimmune diseases and hypersensitivities improve the prognosis in ER-negative breast cancer.

ABSTRACT: Breast cancer (BC) is one of the leading causes of death among women worldwide. Immunostimulatory treatment has increasingly been used as adjuvant therapy in the last few years, in patients with melanoma and other cancer forms, often with an induction of autoimmunity as a consequence of a successful treatment. We aimed at investigating if coexisting autoimmune diseases (AD) or hypersensitivities (HS) similarly to the side effects of immunostimulatory treatment resulted in a better overall survival, compared to patients without these disorders.The patient material used was a consecutive clinical material consisting of 1705 patients diagnosed with BC between 1980 and 2010 in Sweden. The patients were stratified according to coexisting AD, HS or lack of both. Overall survival was calculated using Kaplan-Meier and the Cox proportional hazard model.Our main finding was that BC patients with estrogen receptor (ER) negative tumors together with preexisting AD or HS had a statistically significant better overall survival (HR=0.53; 95% CI= 0.30-0.96) compared to patients without. Premenopausal BC patients with a coexistence of AD or HS had a better overall survival, but this was not statistically significant.For patients with premenopausal or ER-negative BC, coexistence with AD or HS was associated with a better overall survival. Although these findings require validation, and the mechanisms responsible need to be found, they hint to possible new treatment strategies for BC, especially for those with ER-negative tumors and potentially for premenopausal patients.

SUBMITTER: Einefors R

PROVIDER: S-EPMC3755812 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Autoimmune diseases and hypersensitivities improve the prognosis in ER-negative breast cancer.

Einefors Rickard R Kogler Ulrika U Ellberg Carolina C Olsson Håkan H

SpringerPlus 20130730

<h4>Introduction</h4>Breast cancer (BC) is one of the leading causes of death among women worldwide. Immunostimulatory treatment has increasingly been used as adjuvant therapy in the last few years, in patients with melanoma and other cancer forms, often with an induction of autoimmunity as a consequence of a successful treatment. We aimed at investigating if coexisting autoimmune diseases (AD) or hypersensitivities (HS) similarly to the side effects of immunostimulatory treatment resulted in a ...[more]

PMID: 24010029

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Project description:BACKGROUND:In breast cancer, activation of bone morphogenetic protein (BMP) signaling and elevated levels of BMP-antagonists have been linked to tumor progression and metastasis. However, the simultaneous upregulation of BMPs and their antagonist, and the fact that both promote tumor aggressiveness seems contradictory and is not fully understood. METHODS:We analyzed the transcriptomes of the metastatic 66cl4 and the non-metastatic 67NR cell lines of the 4T1 mouse mammary tumor model to search for factors that promote metastasis. CRISPR/Cas9 gene editing was used for mechanistic studies in the same cell lines. Furthermore, we analyzed gene expression patterns in human breast cancer biopsies obtained from public datasets to evaluate co-expression and possible relations to clinical outcome. RESULTS:We found that mRNA levels of the BMP-antagonist Grem1, encoding gremlin1, and the ligand Bmp4 were both significantly upregulated in cells and primary tumors of 66cl4 compared to 67NR. Depletion of gremlin1 in 66cl4 could impair metastasis to the lungs in this model. Furthermore, we found that expression of Grem1 correlated with upregulation of several stem cell markers in 66cl4 cells compared to 67NR cells. Both in the mouse model and in patients, expression of GREM1 associated with extracellular matrix organization, and formation, biosynthesis and modification of collagen. Importantly, high expression of GREM1 predicted poor prognosis in estrogen receptor negative breast cancer patients. Analyses of large patient cohorts revealed that amplification of genes encoding BMP-antagonists and elevation of the corresponding transcripts is evident in biopsies from more than half of the patients and much more frequent for the secreted BMP-antagonists than the intracellular inhibitors of SMAD signaling. CONCLUSION:In conclusion, our results show that GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients. Gremlin1 could represent a novel target for therapy.

Project description:BackgroundTreatment strategies for various subtypes of breast cancer (BC) are different based on their distinct molecular characteristics. Therefore, it is very important to identify key differentially expressed genes (DEGs) between ER-positive/HER2-negative BC and ER-negative/HER2-negative BC.MethodsGene expression profiles of GSE22093 and GSE23988 were obtained from the Gene Expression Omnibus database. There were 74 ER-positive/HER2-negative BC tissues and 85 ER-negative/HER2-negative BC tissues in the two profile datasets. DEGs between ER-positive/HER2-negative tissues and ER-negative/HER2-negative BC tissues were identified by the GEO2R tool. The common DEGs among the two datasets were detected with Venn software online. Next, we made use of the Database for Annotation, Visualization and Integrated Discovery to analyze enriched Kyoto Encyclopedia of Gene and Genome (KEGG) pathways and gene ontology terms. Then, the protein-protein interactions (PPIs) of these DEGs were visualized by Cytoscape with the Search Tool for the Retrieval of Interacting Genes. Of the proteins in the PPI network, Molecular Complex Detection plug-in analysis identified nine core upregulated genes and one core downregulated gene. UALCAN and Gene Expression Profiling Interactive Analysis were applied to determine the expression of these 10 genes in BC. Furthermore, for the analysis of overall survival among those genes, the Kaplan-Meier method was implemented.ResultsNinety-three common DEGs (63 upregulated and 30 downregulated) were identified. KEGG pathway enrichment analysis showed that upregulated DEGs were particularly enriched in the progesterone-mediated oocyte maturation pathway. In addition, PGR might be a prognostic biomarker for ER-positive/HER2-negative BC. CCND1 is a poor prognostic biomarker for ER-positive/HER2-negative BC and ER-negative/HER2-negative BC. Moreover, TFF1, AGR2 and EGFR might be predictive biomarkers of node metastasis in ER-positive/HER2-negative BC and ER-negative/HER2-negative BC.ConclusionsCCND1, AGR2, PGR, TFF1 and EGFR are the key DEGs between ER-positive/HER2-negative BC and ER-negative/HER2-negative BC. Further studies are required to confirm the functions of the identified genes.

Project description:IntroductionTriple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.Materials and methodsThe surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.ResultsPositive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.ConclusionIn TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.

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Autoimmune diseases and hypersensitivities improve the prognosis in ER-negative breast cancer.

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Autoimmune diseases and hypersensitivities improve the prognosis in ER-negative breast cancer.

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