Unknown,Transcriptomics,Genomics,Proteomics

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Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor positive primary breast cancer

ABSTRACT: 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

ORGANISM(S): Homo sapiens

SUBMITTER: Kristina Sørensen

PROVIDER: E-GEOD-48408 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer.

Sørensen Kristina P KP Thomassen Mads M Tan Qihua Q Bak Martin M Cold Søren S Burton Mark M Larsen Martin J MJ Kruse Torben A TA

Breast cancer research and treatment 20131121 3

Expression of HOX transcript antisense intergenic RNA (HOTAIR)--a long non-coding RNA--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 dif ...[more]

PMID: 24258260

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Project description:Purpose To develop a radiosensitivity gene expression assay to predict the response to adjuvant radiotherapy (RT) after breast conserving surgery (BCS) in breast cancer. Patients and methods Fresh frozen primary tumors from 336 patients operated with BCS with or without RT were collected. Patients were split in a discovery cohort (N=172) and a validation cohort (N=164). Genes predicting ipsilateral breast tumor recurrence (IBTR) in an Illumina HT12 v4 whole transcriptome analysis were combined with genes from the literature (248 genes in total) to develop a targeted radiosensitivity assay on the Nanostring nCounter platform. Single sample predictors (SSPs) for IBTR based on a k-top scoring pairs algorithm were trained stratified for estrogen receptor (ER) status and RT. Two previously published profiles (radiosensitivity index, RSI, and radiosensitivity score, RSS) were also tested in our data Results The SSPs were prognostic for IBTR in ER+RT- patients (AUC 0.67, p=0.005), ER+RT- patients (AUC=0.89, p=0.015) and ER-RT+ patients (AUC=0.78, p<0.001). Among ER+ patients, radiosensitive tumors had an excellent effect of RT (p<0.001), while radioresistant tumors had no effect of RT (p=0.4) and a high risk of IBTR (55% at 10 years). Our SSPs developed in ER+ tumors and the RSS correlated with proliferation, while SSPs developed in ER- tumors correlated with immune response. RSI negatively correlated with both proliferation and immune response. Conclusions Our targeted SSPs were prognostic for IBTR and has the potential to stratify patients for RT. The biology behind models may explain the different performance in subgroups of breast cancer. Purpose To develop a radiosensitivity gene expression assay to predict the response to adjuvant radiotherapy (RT) after breast conserving surgery (BCS) in breast cancer. Patients and methods Fresh frozen primary tumors from 336 patients operated with BCS with or without RT were collected. Patients were split in a discovery cohort (N=172) and a validation cohort (N=164). Genes predicting ipsilateral breast tumor recurrence (IBTR) in an Illumina HT12 v4 whole transcriptome analysis were combined with genes from the literature (248 genes in total) to develop a targeted radiosensitivity assay on the Nanostring nCounter platform. Single sample predictors (SSPs) for IBTR based on a k-top scoring pairs algorithm were trained stratified for estrogen receptor (ER) status and RT. Two previously published profiles (radiosensitivity index, RSI, and radiosensitivity score, RSS) were also tested in our data Results The SSPs were prognostic for IBTR in ER+RT- patients (AUC 0.67, p=0.005), ER+RT- patients (AUC=0.89, p=0.015) and ER-RT+ patients (AUC=0.78, p<0.001). Among ER+ patients, radiosensitive tumors had an excellent effect of RT (p<0.001), while radioresistant tumors had no effect of RT (p=0.4) and a high risk of IBTR (55% at 10 years). Our SSPs developed in ER+ tumors and the RSS correlated with proliferation, while SSPs developed in ER- tumors correlated with immune response. RSI negatively correlated with both proliferation and immune response. Conclusions Our targeted SSPs were prognostic for IBTR and has the potential to stratify patients for RT. The biology behind models may explain the different performance in subgroups of breast cancer.

Project description:MCM3 is one of several genes whose expression profile is markedly altered in tamoxifen-resistant breast cancer cell lines. We observed that increased MCM3 expression is associated with tamoxifen resistance. Knockdown of MCM3 resulted in increased susceptibility of tamoxifen-resistant breast cancer cell lines. Moreover, MCM3 expression is significantly associated with clinical outcome of endocrine treated receptor positive breast cancer. To understand the effect of MCM3 on the mechanism of endocrine resistance, we performed gene expression array on tamoxifen-resistant breast cancer cell lines. Here we show that MCM3 knockdown affects the expression of hundreds of genes. Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317) and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

Dataset Information

Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor positive primary breast cancer

Publications

Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer.

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