LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer [array]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE71297 | GEO | 2015/10/01
SECONDARY ACCESSION(S): PRJNA290857
REPOSITORIES: GEO
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Project description:HOTAIR is up-regulated 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 tamoxifen treatment.
2015-10-01 | GSE71276 | 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:This SuperSeries is composed of the SubSeries listed below.
2015-10-01 | GSE71298 | GEO
Project description:Adjuvant tamoxifen is a valid treatment option for women with estrogen receptor (ER)-positive breast cancer. However, up to 40% of patients experience distant or local recurrence or die. MicroRNAs have been suggested to be important prognosticators in breast cancer. This study aims to identify microRNAs with the potential to predict tamoxifen response. We performed a global microRNA screen in primary tumours of six matched pairs of postmenopausal, ER-positive breast cancer patients treated with tamoxifen, who were either recurrence free or had developed a recurrence. Patients were treated at the Robert Bosch Hospital, Stuttgart, Germany, between 1986 and 2005.
2014-07-01 | GSE46823 | GEO
Project description:Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer. However, about 30% of such patients receiving tamoxifen as an adjuvant therapy experience recurrence within 15 years, and most patients with advanced disease eventually develop resistance to tamoxifen. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant human breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive MCF-7/S0.5 cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies. ER+ and tamoxifen sensitive breast cancer cell line (MCF-7/S0.5) and its derived tamoxifen resistant clones: TAMR-1, TAMR-4 and TAMR-8 were miRNA expression profiled in triplicates of each using Exiqon's miRCURY LNA based microRNA Ready-to-use PCR, Human panel I+II, V2.R (Exiqon, product number 203608).
2015-08-01 | E-GEOD-56411 | biostudies-arrayexpress
Project description:Adjuvant tamoxifen is a valid treatment option for women with estrogen receptor (ER)-positive breast cancer. However, up to 40% of patients experience distant or local recurrence or die. MicroRNAs have been suggested to be important prognosticators in breast cancer. This study aims to identify microRNAs with the potential to predict tamoxifen response. We performed a global microRNA screen in primary tumours of six matched pairs of postmenopausal, ER-positive breast cancer patients treated with tamoxifen, who were either recurrence free or had developed a recurrence. Patients were treated at the Robert Bosch Hospital, Stuttgart, Germany, between 1986 and 2005. Total RNA from FFPE tissue from 12 postmenopausal patients with ER-positive breast cancer (6 patients with and 6 patients without recurrence) was extracted. Hybridisation of biotin-labelled RNA was performed on Affymetrix GeneChip miRNA_2.0 Arrays.
2014-07-01 | E-GEOD-46823 | biostudies-arrayexpress
Project description:Expression of HOX transcript antisense intergenic RNA (HOTAIR)—a long intergenic non-coding RNA (lincRNA)—has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that HOTAIR expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers. This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples. In ER-negative tumor samples, it is not possible to detect a prognostic value of HOTAIR expression. These results are successfully validated in an independent dataset with similar associations. Furthermore, we find that high HOTAIR expression is associated with strong positive expression of multiple neighboring HOXC genes of the HOXC locus on chromosome 12q13.13 and have both negative and positive correlation with other genes located on different chromosomes. Independent datasets verify these significant correlations and thus indicate that HOTAIR might regulate additional genes than those previously reported. In conclusion, our findings suggest that HOTAIR expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients. 164 breast cancer samples
2013-11-29 | E-GEOD-48408 | biostudies-arrayexpress
Project description:Tamoxifen is an effective anti-estrogen treatment for patients with estrogen receptor-positive (ER+) breast cancer. However, about 30% of such patients receiving tamoxifen as an adjuvant therapy experience recurrence within 15 years, and most patients with advanced disease eventually develop resistance to tamoxifen. To elucidate the underlying molecular mechanisms of tamoxifen resistance, we performed a systematic analysis of miRNA-mediated gene regulation in three clinically-relevant tamoxifen-resistant human breast cancer cell lines (TamRs) compared to their parental tamoxifen-sensitive MCF-7/S0.5 cell line. Alterations in the expression of 131 miRNAs in tamoxifen-resistant vs. parental cell lines were identified, 22 of which were common to all TamRs using both sequencing and LNA-based quantitative PCR technologies.
2015-08-01 | GSE56411 | GEO
Project description:Expression of HOX transcript antisense intergenic RNA (HOTAIR)—a long intergenic non-coding RNA (lincRNA)—has been examined in a variety of human cancers, and overexpression of HOTAIR is correlated with poor survival among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired with respect to the traditional prognostic markers. We show that HOTAIR expression differs between patients with or without a metastatic endpoint, respectively. Survival analysis shows that high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of prognostic markers. This association is even stronger when looking only at estrogen receptor (ER)-positive tumor samples. In ER-negative tumor samples, it is not possible to detect a prognostic value of HOTAIR expression. These results are successfully validated in an independent dataset with similar associations. Furthermore, we find that high HOTAIR expression is associated with strong positive expression of multiple neighboring HOXC genes of the HOXC locus on chromosome 12q13.13 and have both negative and positive correlation with other genes located on different chromosomes. Independent datasets verify these significant correlations and thus indicate that HOTAIR might regulate additional genes than those previously reported. In conclusion, our findings suggest that HOTAIR expression may serve as an independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.
2013-11-29 | GSE48408 | GEO
Project description:Tamoxifen resistance remains a clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. Tripartite motif-containing (TRIM) proteins are a new class of SUMO E3 ligases, which regulate the SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and the response to tamoxifen remain unclear. In the present study, we observed that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance. Furthermore, TRIM3 overexpression significantly correlated with poor survival of patients with ER+ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking down of TRIM3 reduced these capabilities. Moreover, TRIM3, as a ubiquitin carrier protein 9 (UBC9) binding protein, promoted SUMO modification of estrogen receptor 1 (ESR1) and activated the ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. These results suggest TRIM3 as a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen might provide a potential treatment for breast cancer.
| S-EPMC8433133 | biostudies-literature