A genome-wide cell-free DNA methylation analysis identifies an episignature associated with metastatic luminal B breast cancer.
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ABSTRACT:
PROVIDER: PRJNA885036 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancers of the luminal B subtype are frequent tumors with high proliferation and poor prognosis. Epigenetic alterations have been found in breast tumors and in biological fluids. We aimed to profile the cell-free DNA (cfDNA) methylome of metastatic luminal B breast cancer (LBBC) patients using an epigenomic approach to discover potential noninvasive biomarkers. Plasma cfDNA was analyzed using the Infinium MethylationEpic array (EPIC array) in a cohort of 14 women, including metastatic LBBC patients and healthy controls.
2022-11-16 | GSE214344 | GEO
Project description:Breast cancers of the luminal B subtype are frequent tumors with high proliferation and poor prognosis. Epigenetic alterations have been found in breast tumors and in biological fluids. We aimed to profile the cell-free DNA (cfDNA) methylome of metastatic luminal B breast cancer (LBBC) patients using an epigenomic approach to discover potential noninvasive biomarkers. Plasma cfDNA was analyzed using the Infinium MethylationEpic array in a cohort of 14 women, including metastatic LBBC patients and nontumor controls. The methylation levels of cfDNA and tissue samples were validated with droplet digital PCR. The methylation and gene expression data of 582 primary luminal breast tumors and 79 nontumor tissues were obtained from The Cancer Genome Atlas (TCGA). We found an episignature of 1,467 differentially methylated CpGs that clearly identified patients with LBBC. Among the genes identified, the promoter hypermethylation of WNT1 was validated in cfDNA, showing an area under the ROC curve (AUC) of 0.86 for the noninvasive detection of metastatic LBBC. Both paired cfDNA and primary/metastatic breast tumor samples showed hypermethylation of WNT1. TCGA analysis revealed significant WNT1 hypermethylation in the primary tumors of luminal breast cancer patients, with a negative association between WNT1 methylation and gene expression. In this proof-of-principle study, we discovered an episignature associated with metastatic LBBC using a genome-wide cfDNA methylation approach. We also identified the promoter hypermethylation of WNT1 in cfDNA as a potential noninvasive biomarker for luminal breast cancer. Our results support the use of EPIC arrays to identify new epigenetic noninvasive biomarkers in breast cancer.
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Project description:For many breast cancer (BCa) patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometastatic lesions remain dormant and undetectable yet initiate colonization, are major questions in cancer research. Here we identify and functionally analyse a molecular mechanism involved in bone metastatic latency of estrogen receptor–positive (ER)+ BCa. We developed an in vivo loss-of-function, genome-wide shRNA screening to identify genes relevant for long-latent relapse in BCa. This screen revealed the kinase MSK1 as an important regulator of metastatic dormancy. Importantly, low MSK1 expression associates with early metastasis in ER+ BCa patients. Reduced MSK1 levels impaired cellular differentiation and increased the bone homing and growth capacity of metastatic cells. MSK1 modulates chromatin status at promoters to regulate the expression of luminal differentiation genes, including those for the GATA-3 and FOXA1 transcription factors, which prevent the progression of ER+ BCa towards metastasis. Our results identify the regulation of luminal cell differentiation by MSK1 via modulation of chromatin remodelling to be a key mechanism for controlling metastatic dormancy in BCa. We propose that MSK1 could be a useful marker for stratifying BCa patients as high- or low-risk for early relapse, allowing patients to receive appropriate treatments.
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Project description:The identification of mechanisms controlling breast tumor progression from less aggressive to highly metastatic disease should provide novel therapeutic targets for patients. Here we report the transcriptional corepressor, TLE3, as a critical regulator of cellular plasticity in breast cancer. TLE3 facilitates repression of genes associated with the highly aggressive basal-like breast cancer (BLBC) subtype within luminal cells. Additionally, maintenance of the luminal lineage is dependent on appropriate localization of TLE3 to its transcriptional targets which is mediated through interaction with FOXA1. Furthermore, the ability of TLE3 to repress BLBC transcription results in reduced metastatic capacity and aggressive cellular behaviors. Together our findings establish TLE3 as a critical transcriptional mediator of breast cancer aggressiveness, with TLE3 sustaining the more differentiated and less metastatic nature of luminal tumors through suppression of gene expression programs associated with BLBC.
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Project description:Desmocollin-1 (DSC1) is a desmosomal transmembrane glycoprotein that maintains cell-to-cell adhesion. DSC1 was previously associated with lymph node metastasis of luminal A breast tumors and was found to increase metastatic potential of MCF7 cells in vitro. Therefore, we focused on DSC1 role in cellular and molecular mechanisms in luminal A breast cancer and its possible therapeutic modulation using parthenolide. We performed comparative gene expression analysis using data obtained from RNA-seq of DSC1-overexpressing and control cells treated and untreated with parthenolide in biological duplicates.
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Project description:RET overexpression leads to increased brain metastatic competency in luminal breast cancer patients
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Project description:HT induces an OXPHOS metabolic editing of ER+ breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy In this study, we demonstrated that CD133hi cells can mediate HT resistance and metastatic progression. Using human luminal breast cancer cell lines we have developed an in vivo model of spontaneous metastatic disease recapitulating what is observed in patients. Combining in vivo and in vitro studies we identified a de-novo cancer stem cell population (CSCs) “CD133hi/ERlo/Notch3hi/IL6hi”, which are generated from non-CSCs via the sustained suppression of ER activity. We provide evidence that an ER-IL6-IL6R-CD133 loop is a mechanism mediating HT-resistance.
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Project description:The identification of mechanisms controlling breast tumor progression from less aggressive to highly metastatic disease should provide novel therapeutic targets for patients. Here we report the transcriptional corepressor, TLE3, as a critical regulator of cellular plasticity in breast cancer. TLE3 facilitates repression of genes associated with the highly aggressive basal-like breast cancer (BLBC) subtype within luminal cells. Additionally, maintenance of the luminal lineage is dependent on appropriate localization of TLE3 to its transcriptional targets which is mediated through interaction with FOXA1. Furthermore, the ability of TLE3 to repress BLBC transcription results in reduced metastatic capacity and aggressive cellular behaviors. Together our findings establish TLE3 as a critical transcriptional mediator of breast cancer aggressiveness, with TLE3 sustaining the more differentiated and less metastatic nature of luminal tumors through suppression of gene expression programs associated with BLBC.
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