Targeting long non-coding RNA DANCR inhibits triple negative breast cancer progression

ABSTRACT Triple negative breast cancer (TNBC) is non-responsive to conventional anti-hormonal and Her2-targeted therapies, making it necessary to identify new molecular targets for therapy. Long non-coding RNA anti-differentiation ncRNA (lncRNA DANCR) was identified participating in carcinogenesis of hepatocellular carcinoma, but its expression and potential role in TNBC progression is still unclear. In the present study, our results showed that DANCR expression was increased in TNBC tissues compared with the adjacent normal tissues using quantitative real-time PCR (qRT-PCR) in 63 TNBC specimens. Patients with higher DANCR expression correlated with worse TNM stages as well as a shorter overall survival (OS) using Kaplan–Meier analysis. When the endogenous DANCR was knocked-down via specific siRNA, cell proliferation and invasion were decreased obviously in the MDA-MB-231 cells. In vivo xenograft experiments showed that knockdown of the DANCR in MDA-MB-231 cells reduced the tumor growth significantly. Furthermore, a compendium of TNBC cancer stem cell markers such as CD44, ABCG2 transporter and aldehyde dehydrogenase (ALDH1) were greatly downregulated in the MDA-MB-231 cells with DANCR knockdown. Molecular mechanistic studies revealed that knockdown of DANCR was associated with increased binding of EZH2 on the promoters of CD44 and ABCG2, and concomitant reduction of expression of these genes suggested that they may be DANCR targets in TNBC. Thus, our study demonstrated that targeting DANCR expression might be a viable therapeutic approach to treat triple negative breast cancer. Summary: Targeting LncRNA DANCR obstructs triple negative breast cancer progression by down-regulating cancer stem cell marker CD44 and ABCG2.

[1]  C. Xiao,et al.  LncRNA UCA1 promotes epithelial-mesenchymal transition (EMT) of breast cancer cells via enhancing Wnt/beta-catenin signaling pathway. , 2016, European review for medical and pharmacological sciences.

[2]  B. Krishnamachary,et al.  Phototheranostics of CD44-positive cell populations in triple negative breast cancer , 2016, Scientific Reports.

[3]  W. Fang,et al.  Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment , 2016, Oncotarget.

[4]  Peng Guo,et al.  Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3 , 2016, Oncotarget.

[5]  Lin Zhang,et al.  Long noncoding RNA LINP1 regulates double strand DNA break repair in triple negative breast cancer , 2016, Nature Structural &Molecular Biology.

[6]  Quentin Liu,et al.  Inhibition of Sonic Hedgehog Signaling Pathway by Thiazole Antibiotic Thiostrepton Attenuates the CD44+/CD24-Stem-Like Population and Sphere-Forming Capacity in Triple-Negative Breast Cancer , 2016, Cellular Physiology and Biochemistry.

[7]  Yongmei Yin,et al.  LncRNAs as new biomarkers to differentiate triple negative breast cancer from non-triple negative breast cancer , 2016, Oncotarget.

[8]  Gwyn T. Williams,et al.  The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cells , 2016, Oncotarget.

[9]  Shuhan Sun,et al.  Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1 , 2016, Hepatology.

[10]  X. Shu,et al.  ALDH1A1 mRNA expression in association with prognosis of triple-negative breast cancer , 2015, Oncotarget.

[11]  Yang Liu,et al.  Over-expression of lncRNA DANCR is associated with advanced tumor progression and poor prognosis in patients with colorectal cancer. , 2015, International journal of clinical and experimental pathology.

[12]  Bin Chen,et al.  ABCG2 transporter inhibitor restores the sensitivity of triple negative breast cancer cells to aminolevulinic acid-mediated photodynamic therapy , 2015, Scientific Reports.

[13]  Xiaokun Shen,et al.  Identification of novel long non-coding RNAs in triple-negative breast cancer , 2015, Oncotarget.

[14]  J. Rinn,et al.  Discovery and annotation of long noncoding RNAs , 2015, Nature Structural &Molecular Biology.

[15]  I. Mayer,et al.  Platinum agents in the treatment of early-stage triple-negative breast cancer: is it time to change practice? , 2014, Clinical advances in hematology & oncology : H&O.

[16]  J. Ingle,et al.  Inhibition of Cdk2 kinase activity selectively targets the CD44+/CD24−/Low stem-like subpopulation and restores chemosensitivity of SUM149PT triple-negative breast cancer cells , 2014, International journal of oncology.

[17]  Chung-Han Lee,et al.  Clinicopathologic Characteristics of Breast Cancer Stem Cells Identified on the Basis of Aldehyde Dehydrogenase 1 Expression , 2014, Journal of breast cancer.

[18]  Etienne Rouleau,et al.  PIK3R1 underexpression is an independent prognostic marker in breast cancer , 2013, BMC Cancer.

[19]  Bing-he Xu,et al.  Stem Cell Marker Aldehyde Dehydrogenase 1 (ALDH1)-Expressing Cells are Enriched in Triple-Negative Breast Cancer , 2013, The International journal of biological markers.

[20]  M. Naylor,et al.  Breast cancer stem cells , 2013, Front. Physiol..

[21]  Y. Mo,et al.  Negative regulation of lncRNA GAS5 by miR-21 , 2013, Cell Death and Differentiation.

[22]  A. Meeson,et al.  Breast cancer, side population cells and ABCG2 expression. , 2012, Cancer letters.

[23]  Howard Y. Chang,et al.  Suppression of progenitor differentiation requires the long noncoding RNA ANCR. , 2012, Genes & development.

[24]  M. Ringnér,et al.  The CD44+/CD24- phenotype is enriched in basal-like breast tumors , 2008, Breast Cancer Research.

[25]  H. Tsuda,et al.  Gene expression profiles with cDNA microarray reveal RhoGDI as a predictive marker for paclitaxel resistance in ovarian cancers. , 2006, Oncology reports.

[26]  M. Ladanyi,et al.  Validation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts. , 2006, Diagnostic molecular pathology : the American journal of surgical pathology, part B.