Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE270229 | GEO | 2024/09/03
REPOSITORIES: GEO
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Project description:Deciphering the molecular mechanisms involved in breast tumorigenesis has been the subject of extensive research in the last years; yet unpredictable response and development of resistance to adjuvant therapies remain major questions in the management of breast cancer patients. The power of miR expression signatures has emerged recently from several studies. Normal and breast tumor tissues can be discriminated by a miR signature as reported by Iorio et al (Iorio et al, 2005). Recent findings have also linked deregulated miR expression to breast cancer metastasis (Adorno et al, 2009; Huang et al, 2008; Tavazoie et al, 2008). Moreover, microRNAs are considering as a powerful tool in diagnosis and prognosis of breast cancer. In our study, we measured microRNA expression profiles from 64 primary breast cancer patients, comprising 56 matched tumor and adjacent peritumoral breast tissues, 5 tumor and 3 peritumor unmatched tissues. Our aim was to identify new microRNAs involved in the process of neoplastic transformation. The microarray data analysis identified, in every subgroup of breast cancers analyzed, a specific subset of microRNAs that were differentially expressed in tumor compared to peritumoral tissues. Among these miRs, we identified two (miR-10b* and miR-139-5p) that were down-regulated and three (miR-425, miR-454 and miR-301a) that were up-regulated for all three subtypes. We further show that microRNA-10b* is a master regulator of breast cancer cell proliferation. Two canonical CpG islands (5kb) upstream from the precursor sequence are hypermethylated in breast cancer tissues analyzed. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumors inhibits cell proliferation and impairs tumor growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b*, BUB1, PLK1 and CCNA2 genes, which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients reduced disease free survival, relapse free survival and metastasis free survival when compared to low expressors. This also suggests that restoration of microRNA-10b* expression might bear therapeutic promise. In exploring the potential involvement of miRs in breast tumorigenesis, we profiled the miRs expression of 64 primary breast cancer patients, comprising 56 matched tumor and adjacent peritumoral breast tissues, 5 tumor and 3 peritumor unmatched tissues, using the Agilent microarray platform. For 14 samples technical replicate were also performed.
2012-10-30 | E-GEOD-40525 | biostudies-arrayexpress
Project description:Abstract:
Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system - as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example - have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed "immune-mediated" theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti- and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor "education" of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the pro-tumor effects of the immune system in metastatic cancer.
2024-09-02 | BIOMD0000000926 | BioModels
Project description:Deciphering the molecular mechanisms involved in breast tumorigenesis has been the subject of extensive research in the last years; yet unpredictable response and development of resistance to adjuvant therapies remain major questions in the management of breast cancer patients. The power of miR expression signatures has emerged recently from several studies. Normal and breast tumor tissues can be discriminated by a miR signature as reported by Iorio et al (Iorio et al, 2005). Recent findings have also linked deregulated miR expression to breast cancer metastasis (Adorno et al, 2009; Huang et al, 2008; Tavazoie et al, 2008). Moreover, microRNAs are considering as a powerful tool in diagnosis and prognosis of breast cancer. In our study, we measured microRNA expression profiles from 64 primary breast cancer patients, comprising 56 matched tumor and adjacent peritumoral breast tissues, 5 tumor and 3 peritumor unmatched tissues. Our aim was to identify new microRNAs involved in the process of neoplastic transformation. The microarray data analysis identified, in every subgroup of breast cancers analyzed, a specific subset of microRNAs that were differentially expressed in tumor compared to peritumoral tissues. Among these miRs, we identified two (miR-10b* and miR-139-5p) that were down-regulated and three (miR-425, miR-454 and miR-301a) that were up-regulated for all three subtypes. We further show that microRNA-10b* is a master regulator of breast cancer cell proliferation. Two canonical CpG islands (5kb) upstream from the precursor sequence are hypermethylated in breast cancer tissues analyzed. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumors inhibits cell proliferation and impairs tumor growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b*, BUB1, PLK1 and CCNA2 genes, which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients reduced disease free survival, relapse free survival and metastasis free survival when compared to low expressors. This also suggests that restoration of microRNA-10b* expression might bear therapeutic promise.
2012-10-30 | GSE40525 | GEO
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. Sequencing miRNAs from Human breast cancer cells: MCF10A, MCF7, MDA-MB-231, MDA-MB-LM2
2013-11-15 | E-GEOD-42313 | biostudies-arrayexpress
Project description:In our study, We found that exosomal transfer occurred from highly metastatic nasopharyngeal carcinoma (NPC) cells to poorly metastatic NPC cells mediates cell-cell communication and therefore enhanced metastasis potential and decreased intracellular ROS levels of low metastatic NPC cells. To investigate the detailed mechanism of exosomes derived from highly metastatic NPC cells (H-exo) mediated low metastatic NPC cells metastasis and ROS reduction, low metastatic NPC cells 6-10B and S26 were treated with or without H-exo for RNA-SEQ analysis to exame the expression of metastasis- and ROS-related genes. Our results indicate that the levels of the "leading edge" genes that the majority of these genes correlated with ROS suppressing genes were significantly increased in H-exo treated 6-10B and S26 cells. In contrast, the expression levels of ROS production promoting gene were significantly lower in H-exo treated 6-10B and S26 cells than untreated 6-10B and S26 cells. Meanwhile, the majority of the genes correlated with anti-apoptotic responses and pro-metastasis could be potentially up-regulated by treated 6-10B and S26 cells with H-exo.
2020-05-02 | GSE149714 | GEO
Project description:Introduction: MicroRNAs (miRNAs) are small, non-coding RNA molecules involved in post-transcriptional gene regulation and have recently been shown to play a role in cancer metastasis. In solid tumors, especially breast cancer, alterations in miRNA expression contribute to cancer pathogenesis, including metastasis. Considering the emerging role of miRNAs in metastasis, the identification of predictive markers is necessary to further understanding of stage-specific breast cancer development. This is a retrospective analysis that aimed to identify molecular biomarkers related to distant breast cancer metastasis development.<br><br>Methods: A retrospective case cohort study was performed in 64 breast cancer patients treated during the period from 1998-2001. The case group (n=29) consisted of patients with a poor prognosis who presented with breast cancer recurrence or metastasis during follow up. The control group (n=35) consisted of a random sample of patients with a good prognosis who did not develop breast cancer recurrence or metastasis. These patient groups were stratified according to TNM clinical stage (CS) I, II and III, and the main clinical features of the patients were homogeneous. miRNA profiling was performed using formalin-fixed, paraffin-embedded tumors. Biomarkers related to metastatic potential were identified independent of clinical stage, and a cutoff point was selected based on the optimal sensitivity and specificity (ROC curve). Finally, a hazard risk analysis of these biomarkers was performed to evaluate their relation to metastatic potential. <br><br>Results: miRNA expression profiling identified several miRNAs that were either specific and shared across all clinical stages (p?0.05). Among these, we identified miRNAs previously associated with cell motility (let-7 family), cell proliferation and invasion (hsa-miR-16 and has-miR-205) and distant metastasis (hsa-miR-21). In addition, hsa-miR-494 and hsa-miR-21 were up-regulated in metastatic cases of CSI and II. Furthermore, the combination of the 3 miRNAs identified for CSII (hsa-miR-494, hsa-miR-183 and hsa-miR-21) was significant and were a more effective risk marker compared to the single miRNAs. <br><br>Conclusions: Women with metastatic breast cancer, especially CSII, presented up-regulated levels of miR-183, miR-494 and miR-21, which were associated with a poor prognosis. These miRNAs therefore represent new risk biomarkers of breast cancer metastasis and may be useful for future targeted therapies.
2013-08-07 | E-MEXP-3947 | biostudies-arrayexpress
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:Abstract Maspin is a tumor and metastasis suppressor playing an essential role as gatekeeper of tumor progression. It is highly expressed in epithelial cells but is silenced in the onset of metastatic disease by epigenetic mechanisms. Reprogramming of Maspin epigenetic silencing offers a therapeutic potential to lock metastatic progression. Herein we have investigated the ability of the Artificial Transcription Factor 126 (ATF-126) designed to upregulate the Maspin promoter to inhibit tumor progression in pre-established breast tumors in immunodeficient mice. ATF-126 was transduced in the aggressive, mesenchymal-like and triple negative breast cancer line, MDA-MB-231. Induction of ATF expression in vivo by Doxycycline resulted in 50% reduction in tumor growth and totally abolished tumor cell colonization. Genome-wide transcriptional profiles of ATF-induced cells revealed a gene signature that was found over-represented in estrogen receptor positive (ER+) “Normal-like” intrinsic subtype of breast cancer and in poorly aggressive, ER+ luminal A breast cancer cell lines. The comparison transcriptional profiles of ATF-126 and Maspin cDNA defined an overlapping 19-gene signature, comprising novel targets downstream the Maspin signaling cascade. Our data suggest that Maspin up-regulates downstream tumor and metastasis suppressor genes that are silenced in breast cancers, and are normally expressed in the neural system, including CARNS1, SLC8A2 and DACT3. In addition, ATF-126 and Maspin cDNA induction led to the re-activation of tumor suppressive miRNAs also expressed in neural cells, such as miR-1 and miR-34, and to the down-regulation of potential oncogenic miRNAs, such as miR-10b, miR-124, and miR-363. As expected from its over-representation in ER+ tumors, the ATF-126-gene signature predicted favorable prognosis for breast cancer patients. Our results describe for the first time an ATF able to reduce tumor growth and metastatic colonization by epigenetic reactivation of a dormant, normal-like, and more differentiated gene program.
2011-08-23 | GSE27842 | GEO
Project description:To identify genes differentially modulated by anti-miR-182 treatment in a liver melanoma metastasis mouse model. Targeting oncogenic microRNAs is emerging as a promising strategy for cancer therapy. Here we provide proof-of-principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the effect of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, whose silencing represses invasion and induces apoptosis in vitro. In particular, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2â sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had an appreciably lower burden of liver metastases compared to the control. We confirmed that miR-182 levels were effectively downregulated in the anti-miR treated tumors relative to the scrambled treated tumor both in the liver and in the spleen. This downregulation was accompanied by an upregulation of miR-182 direct targets. Transcriptome analysis of mouse tissues treated with anti-miR-182 or scramble oligonucleotides revealed an enrichment for genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of target levels. Our results suggest that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide solid proof-of-principle for similar strategies against other metastatic tumors. Keywords: Differentially expressed genes (mRNAs) in response to miRNA inhibition Quadruplicate (n=4) samples of anti-miR-182 treated human melanoma metastasis compared to quadruplicate control treated metastasis.
2010-10-21 | E-GEOD-24824 | biostudies-arrayexpress
Project description:High metastatic nasopharyngeal carcinoma cell line 5-8F expression patterns against low metastatic nasopharyngeal carcinoma cell line 6-10B. This study was done to screen genes related with metastasis in NPC. The microarray analyses were done in a same batch. 6-10B cells are cultured and harvested at three different time points.
2009-12-10 | E-GEOD-15903 | biostudies-arrayexpress