Similar Datasets
Project description:HOTAIR is a 2.2-kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We show that sustained high levels of HOTAIR over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of HOTAIR overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted EMT. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program. Targeting HOTAIR lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.
| S-EPMC9831604 | biostudies-literature
Project description:Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis
| PRJNA833338 | ENA
Project description:Triple Negative Breast cancer accounts for some of the most aggressive types of breast cancer. By interrogating clinical datasets, we found that the activities of p63 and Hypoxia-Inducible-Factors (HIFs), two master regulators of the invasive and metastatic cancer cell phenotype are linked in TNBC through the p63-target Sharp1. Mechanistically, Sharp1 promotes HIF-1α/HIF-2α proteasomal degradation by serving as HIFs presenting factor to the proteasome independently from oxygen levels and prior ubiquitination. To investigate unbiasedly if Sharp1 is a general inhibitor of HIF induced transcriptional program, we compared the transcriptomic profile of cells either overexpressing Sharp1 or depleted of HIF1a and HIF2a. We collected RNA from control MDA-MB-231 cells (shGFP) or MDA-MB-231 cells overexpressing Sharp1 or MDA-MB-231 cells depleted of HIF1a and HIF2a (shHIF). Cells were left untreated in normal culturing conditions before harvesting. Samples were then processed for total RNA extraction and hybridization on Affymetrix microarrays. Four biological replicas (A, B, C, D) were used for each of the 4 conditions (1: shGFP, control cells; 2: shHIF cells; 3: Sharp1-overexpressing cells) for a total of 12 samples.
| S-ECPF-GEOD-33950 | biostudies-other
Project description:Triple Negative Breast cancer accounts for some of the most aggressive types of breast cancer. By interrogating clinical datasets, we found that the activities of p63 and Hypoxia-Inducible-Factors (HIFs), two master regulators of the invasive and metastatic cancer cell phenotype are linked in TNBC through the p63-target Sharp1. Mechanistically, Sharp1 promotes HIF-1α/HIF-2α proteasomal degradation by serving as HIFs presenting factor to the proteasome independently from oxygen levels and prior ubiquitination. To investigate unbiasedly if Sharp1 is a general inhibitor of HIF induced transcriptional program, we compared the transcriptomic profile of cells either overexpressing Sharp1 or depleted of HIF1a and HIF2a. We collected RNA from control MDA-MB-231 cells (shGFP) or MDA-MB-231 cells overexpressing Sharp1 or MDA-MB-231 cells depleted of HIF1a and HIF2a (shHIF). Cells were left untreated in normal culturing conditions before harvesting. Samples were then processed for total RNA extraction and hybridization on Affymetrix microarrays. Four biological replicas (A, B, C, D) were used for each of the 4 conditions (1: shGFP, control cells; 2: shHIF cells; 3: Sharp1-overexpressing cells) for a total of 12 samples.
2012-07-18 | E-GEOD-33950 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-22 | GSE106517 | GEO
Project description:Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.
| S-EPMC4791209 | biostudies-literature
Project description:Triple Negative Breast cancer accounts for some of the most aggressive types of breast cancer. By interrogating clinical datasets, we found that the activities of p63 and Hypoxia-Inducible-Factors (HIFs), two master regulators of the invasive and metastatic cancer cell phenotype are linked in TNBC through the p63-target Sharp1. Mechanistically, Sharp1 promotes HIF-1α/HIF-2α proteasomal degradation by serving as HIFs presenting factor to the proteasome independently from oxygen levels and prior ubiquitination. To investigate unbiasedly if Sharp1 is a general inhibitor of HIF induced transcriptional program, we compared the transcriptomic profile of cells either overexpressing Sharp1 or depleted of HIF1a and HIF2a.
2012-07-19 | GSE33950 | GEO
Project description:N6-methyladenosine (m6A) modification of RNA regulates normal and cancer biology, but knowledge of its function on long noncoding RNAs (lncRNAs) remains limited. Here, we reveal that m6A regulates the breast cancer-associated human lncRNA HOTAIR. Mapping m6A in breast cancer cell lines, we identify multiple m6A sites on HOTAIR, with 1 single consistently methylated site (A783) that is critical for HOTAIR-driven proliferation and invasion of triple-negative breast cancer (TNBC) cells. Methylated A783 interacts with the m6A "reader" YTHDC1, promoting chromatin association of HOTAIR, proliferation and invasion of TNBC cells, and gene repression. A783U mutant HOTAIR induces a unique antitumor gene expression profile and displays loss-of-function and antimorph behaviors by impairing and, in some cases, causing opposite gene expression changes induced by wild-type (WT) HOTAIR. Our work demonstrates how modification of 1 base in an lncRNA can elicit a distinct gene regulation mechanism and drive cancer-associated phenotypes.
| S-EPMC9731500 | biostudies-literature
Project description:We assessed the effects of chewing behavior on the lung-metastasis-promoting impact of chronic psychological-stress in mice. Human breast-cancer cells (MDA-MB-231) were injected into the tail vein of female nude mice. Mice were randomly divided into stress, stress-with-chewing, and control groups. We created chronic stress by placing mice in small transparent tubes for 45 min, 3 times a day for 7 weeks. Mice in the stress-with-chewing group were allowed to chew wooden sticks during the experimental period. The histopathological examination showed that chronic psychological-stress increased lung metastasis, and chewing behavior attenuated the stress-related lung metastasis of breast-cancer cells. Chewing behavior decreased the elevated level of the serum corticosterone, normalized the increased expression of glucocorticoid, and attenuated the elevated expression of adrenergic receptors in lung tissues. We also found that chewing behavior normalized the elevated expression of inducible nitric oxide synthase, 4-hydroxynonenal, and superoxide dismutase 2 in lung tissues, induced by chronic stress. The present study demonstrated that chewing behavior could attenuate the promoting effects of chronic psychological-stress on the lung metastasis of breast-cancer cells, by regulating stress hormones and their receptors, and the downstream signaling-molecules, involving angiogenesis and oxidative stress.
| S-EPMC9740082 | biostudies-literature
Project description:PurposeThis study was to investigate the effects of lncRNA TPA overexpression and knockdown in stable transfected cell lines on the EMT, migration and invasion capabilities of breast cancer cells.MethodsWB and qRT-PCR were used to detect the expression of E-cadherin, Vimentin, fibronectin and N-cadherin, the key molecules of EMT, to determine whether lncRNA regulates EMT; scratch, migration and invasion assay were used to detected the effect of lncRNA TPA on the migration and invasion of breast cancer cells. The effect of lncRNA TPA on breast cancer metastasis was observed in nude mice model. Pierce Magnetic RNA-Protein Pull-Down Kit was used to bind the 3'-terminal desulfurized biotin-labeled lncRNA TPA with Magnetic beads, and then incubated with the proteins extracted from cell line C and D, respectively. After elution of the binding proteins, the interacting proteins were further identified by mass spectrometry to screen out the interacting proteins. The candidate proteins were expressed and purified in vitro, and the interaction between lncRNA-candidate proteins were verified by RNA-EMSA.ResultsOverexpression of lncRNA TPA decreased the expression of E-cadherin, and significantly increased the expression of Vimentin, fibronectin and TGF-β1 (p < 0.01), and increased the migration rate, migration ability and invasion ability of cell group (P < 0.01). Multiple lung metastases were observed in the lung tissue of nude mice with overexpression of lncRNA TPA.ConclusionLncRNA TPA affects the occurrence of breast cancer EMT through TGF-β signaling pathway, and then promotes the invasion and metastasis of breast cancer. LncRNA TPA may affect the corresponding signaling pathways through one or more interacting proteins, and ultimately promote the invasion and metastasis of breast cancer.
| S-EPMC8378314 | biostudies-literature