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Suppression of miRNA-708 by polycomb group promotes metastases by calcium-induced cell migration

ABSTRACT: The progression of cancer to metastatic disease is a major cause of death. We identified miR-708 being transcriptionally repressed by polycomb repressor complex (PRC2)-induced H3-K27 trimethylation in metastatic breast cancer. miR-708 targets the endoplasmic reticulum protein neuronatin (Nnat) to decrease intracellular calcium (Ca2+) level, resulting in reduction of activation of ERK and FAK, decreased cell migration, and impaired metastases. Functional complementation experiments with Nnat-3’UTR mutant, which is refractory to suppression by miR-708, rescued cell migration and metastasis defects. In breast cancer patients, miR-708 expression was decreased in lymph node and distal metastases, suggesting a metastasis-suppressive role. Our findings uncover a mechanistic role for miR-708 in metastasis and provide a rationale for developing miR-708 as a therapeutic agent against metastatic breast cancer. Sequencing miRNAs from Human breast cancer cells: MCF10A, MCF7, MDA-MB-231, MDA-MB-LM2

ORGANISM(S): Homo sapiens

SUBMITTER: Dingcheng Gao

PROVIDER: E-GEOD-42313 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Suppression of miRNA-708 by polycomb group promotes metastases by calcium-induced cell migration

Project description:The progression of cancer to metastatic disease is a major cause of death. We identified miR-708 being transcriptionally repressed by polycomb repressor complex (PRC2)-induced H3-K27 trimethylation in metastatic breast cancer. miR-708 targets the endoplasmic reticulum protein neuronatin (Nnat) to decrease intracellular calcium (Ca2+) level, resulting in reduction of activation of ERK and FAK, decreased cell migration, and impaired metastases. Functional complementation experiments with Nnat-3’UTR mutant, which is refractory to suppression by miR-708, rescued cell migration and metastasis defects. In breast cancer patients, miR-708 expression was decreased in lymph node and distal metastases, suggesting a metastasis-suppressive role. Our findings uncover a mechanistic role for miR-708 in metastasis and provide a rationale for developing miR-708 as a therapeutic agent against metastatic breast cancer.

2013-11-15 | GSE42313 | GEO

Project description:We have used a unique metastasis model system in combination with quantitative, comparative proteomics to identify novel markers associated with the ability of cancer cells to colonize and form metastasis, and subsequently analyzed the clinical relevance of these proteins using breast cancer biopsies from patients with known clinical outcome within a 10-year follow-up. The model system consists of two isogenic human breast cancer cell lines that are equally tumorigenic in mice, but one gives rise to metastasis while the other disseminates single cells that remain dormant in distant organs. Using stable isotopic labeling by amino acids in cell culture and subcellular fractionation, the nuclear, cytosol and mitochondria proteomes were analyzed by LC-MS/MS, identifying seven proteins that exhibited altered expression between the cell lines, including L-lactate dehydrogenase A, NADH-cytochrome b5 reductase 3 (CYB5R3), niemann-pick c1 protein, and nucleolar RNA helicase 2.

2015-09-14 | PXD001391 | Pride

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

Project description:Bone is the primary site of breast cancer metastasis and complications associated with bone metastases can lead to a significantly decreased quality of life in these patients. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene expression profiles from laser capture micro-dissected trephine biopsies of both breast cancer bone metastases and primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared to primary mammary tumors. Results: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary mammary tumors. In addition, ABCC5 was significantly up-regulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 significant reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers. Conclusions: Our data, for the first time, suggests that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for the efficient bone resorption mediated by osteoclasts. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis. primary breast tumors vs. bone trephine biopsies

2012-11-09 | E-GEOD-39494 | biostudies-arrayexpress

Stress hormones induce breast intra-tumor heterogeneity

Project description:Diversity within or between a tumour and metastases, known as intra-patient tumour heterogeneity develops during disease progression, and is a serious hurdle for therapy1,2,3. Metastasis is the fatal hallmark of cancer and mechanisms of colonization, the most complex step of the metastatic cascade4,5, remain ill-defined. Better understanding of cellular and molecular processes underlying intra-patient tumour heterogeneity and metastasis are pivotal for the success of personalized cancer treatment. Here, transcriptional profiling of tumours and matched metastases showed cancer site-specific phenotypes, and identified increased glucocorticoid receptor (GR) activity in the distant metastases. GR has been shown to mediate the effects of stress hormones and of their synthetic derivatives, widely used in the clinic as anti-inflammatory and immunosuppressive.

2019-03-25 | PXD009102 | Pride

The murine metastatic microenvironment of experimental brain metastases in breast cancer differs by host age in vivo: A proteomic study.

Project description:Breast cancer in young patients is known to exhibit more aggressive biological behavior and is associated with a less favorable prognosis than the same disease in older patients, owing in part to an increased incidence of brain metastases, the mechanistic explanations behind which remain poorly understood. We recently reported that young mice, compared to older mice, showed about a three-fold increase in the development of brain metastases in mouse models of triple-negative and luminal B breast cancer. Here we have performed a quantitative mass spectrometry-based proteomic analysis to identify proteins contributing to age-related disparities in the development of breast cancer brain metastases. Using a mouse model of brain-tropic (MDA-MB-231BR) triple-negative breast cancer, we harvested subpopulations of tumor metastases, the tumor-adjacent metastatic microenvironment, and uninvolved brain tissues via laser microdissection followed by quantitative proteomic analysis using high resolution mass spectrometry to characterize differentially abundant proteins contributing to age-dependent rates of brain metastasis.

2024-01-11 | PXD042346 | Pride

A microRNA/circle RNA axis promotes metastasis through CDR1-mediated anoikis-resistance

Project description:Lung cancer is an intrinsically highly metastatic disease and the leading cause of cancer-related deaths worldwide. Although discovery of molecular aberrations in lung adenocarcinomas has led to development of effective targeted therapies, corresponding “drivers” in lung squamous carcinomas (LUSC) have not materialized. Extensive molecular profiling has revealed LUSC tumors have non-recurrent somatic mutations and are largely driven by copy number alterations. Because microRNAs (miRs) play increasingly important roles in regulating metastasis-relevant pathways, we evaluated whether miRs can regulate LUSC progression. By integrating bioinformatics of the Cancer Genome Atlas (TCGA) with novel, highly metastatic LUSC models, we found that miR-671-5p is a key inhibitor of LUSC metastasis. Surprisingly, miR-671-5p regulates LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of CDR1as is through miR-7 sponging, we found miR-671-5p more potently silences an axis of CDR1as and its anti-sense transcript, cerebellar degeneration related antigen 1 (CDR1). To our knowledge, no function of CDR1 has ever been described. We found loss of CDR1as and CDR1 significantly inhibited LUSC metastases. Intriguingly, CDR1 was strongly associated with an epithelial-mesenchymal transition (EMT) program in LUSC tumors, and was sufficient to promote metastases, increased migration and substrate-independent survival, known as anoikis-resistance. CDR1, which directly interacts with AP1 and COPI subunits, no longer promoted migration and anoikis-resistance upon blockade of Golgi trafficking. Our findings reveal a miR/circRNA axis that regulates LUSC metastases through an enigmatic protein, CDR1.

2021-09-08 | PXD012286 | Pride

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

2012-11-09 | GSE39494 | GEO

Predicting the evolution of metastatic disease in breast cancer: results from 50 years of autopsies

Project description:This is a genomic analysis of breast cancer metastasis using array based CGH and is part of a large study investigating the patterns and evolution of metastases from breast cancer using autopsy material accumulated over the last 50 years from a single institution. The samples used in the genomic profiling comprise the primary breast tumour and multiple matched metastases from each patient. The data demonstrate both the clonal nature of metastatic progression and the role of clonal evolution during progression. This study comprises six patients who died of metastatic breast cancer. For some patients the breast primary tumour and lymph node metastasis was obtained from previous surgical excision, otherwise material was obtained from a resulting autopsy. Each patient set of samples involves the primary breast tumour and multiple metastases, including from lung, liver, lymph node, adrenal gland, brain etc. DNA was extracted from formalin fixed paraffin embedded (FFPE) tissue blocks and analysed for DNA copy number alterations using an Agilent aCGH platform.

2013-11-11 | E-GEOD-46826 | biostudies-arrayexpress

Prognostic value of biomarkers EpCAM and B-crystallin is associated with lymphatic metastasis in breast cancer by iTRAQ analysis

Project description:Metastasis is responsible for the majority of deaths in a variety of cancer types, including breast cancer. Although several factors or biomarkers have been identified to predict the outcome of patients with breast cancer, few studies have been conducted to identify metastasis-associated biomarkers. Quantitative iTRAQ proteomics analysis was used to detect differentially expressed proteins between lymph node metastases and their paired primary tumor tissues from 23 patients with metastatic breast cancer. Immunohistochemistry was performed to validate the expression of two upregulated (EpCAM, FADD) and two downregulated (NDRG1, αB-crystallin) proteins in 190 paraffin-embedded tissue samples. These four proteins were further analyzed for their correlation with clinicopathological features in 190 breast cancer patients. We identified 637 differentially regulated proteins (397 upregulated and 240 downregulated) in lymph node metastases compared with their paired primary tumor tissues. Furthermore, bioinformatics analysis using GEO profiling confirmed the difference in the expression of EpCAM between metastases and primary tumors tissues. Two upregulated (EpCAM, FADD) and two downregulated (NDRG1, αB-crystallin) proteins were associated with the progression of breast cancer. Obviously, EpCAM plays a role in the metastasis of breast cancer cells to the lymph node. We further identified αB-crystallin as an independent biomarker to predict lymph node metastasis and the outcome of breast cancer patients.

2019-08-29 | PXD013931 | Pride

WG-DASL expression profiling of formalin-fixed paraffin embedded primary breast tumours and matched lymph node metastases across four clinically relevant metastatic groups

Project description:The development of metastases is a complex multi-step process manifested by diverse patterns, involving single or multiple organs and different time-courses of distant recurrences. The aim of this study was to characterise molecular patterns associated with patterns of organ-specific metastatic spread observed in the clinic from FFPE embedded breast carcinomas and lymph node metastases. This study includes patients with four patterns of first metastatic sites: bone only (with no visceral metastases within 6 months of first metastasis); to viscera only (with no bone metastasis within 6 months of first metastasis); to bone and visceral organs within a 6 month period; and no recorded distant metastasis. The study population was composed of 5,061 patients diagnosed with invasive primary breast cancer without distant metastasis at the time of diagnosis between 1975 and 2005 from Guyâs Hospital. From the study population, an incidence-based case-control design was used to include patients from each of the metastatic groups and a control series randomly matched to cases according to having no reported metastasis up to the calendar date of metastasis. The aim of this expression profiling study was to characterise any molecular patterns that may be associated with the organ-specific metastatic spread observed in the clinic from FFPE embedded breast carcinomas and lymph node metastases.

2017-12-01 | E-MTAB-4003 | biostudies-arrayexpress

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