Estrogen Receptor α Regulates ATM Expression through miRNAs in Breast Cancer

Purpose: Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER-negative breast cancers display more aggressive clinical behaviors and are resistant to antiestrogen therapies. In addition, many ER-negative tumors show insensitivity to many chemotherapeutic drugs and radiotherapy, although mechanisms underlying this phenotype are less clear. Experimental Design: We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. On the basis of the clinical data, we conducted siRNA knockdown to study the role of ERα on ATM expression in breast cancer cell lines. Furthermore, we used antisense oligonucleotides against micro RNAs (miRNA) or miRNA overexpression plasmids to study the role of miR-18a and -106a on ATM expression. Finally we used in situ hybridization to assess miR-18a and -106a expression in breast cancer tissues. Results: We found that in ER-negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage-response protein, is aberrantly upregulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we showed that ERα, but not ERβ, negatively regulates ATM expression. Furthermore, we identified that ERα activates miR-18a and -106a to downregulate ATM expression. We also showed that miR-18a and -106a were significantly underexpressed in ER-negative breast cancer tissues. Conclusions: We reveal a novel mechanism involving ERα and miR-18a and -106a regulation of ATM in breast cancer. Clin Cancer Res; 19(18); 4994–5002. ©2013 AACR.

[1]  P. Ascenzi,et al.  Estrogen signaling multiple pathways to impact gene transcription. , 2006, Current genomics.

[2]  Libing Song,et al.  miR-18a Impairs DNA Damage Response through Downregulation of Ataxia Telangiectasia Mutated (ATM) Kinase , 2011, PloS one.

[3]  Y. Shiloh The ATM-mediated DNA-damage response: taking shape. , 2006, Trends in biochemical sciences.

[4]  Sheng Tan,et al.  Pivotal role of reduced let-7g expression in breast cancer invasion and metastasis. , 2011, Cancer research.

[5]  M. Lavin,et al.  Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer , 2008, Nature Reviews Molecular Cell Biology.

[6]  A. Maggi Liganded and unliganded activation of estrogen receptor and hormone replacement therapies. , 2011, Biochimica et biophysica acta.

[7]  G. Hannon,et al.  The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response , 2009, Proceedings of the National Academy of Sciences.

[8]  H. Nevanlinna,et al.  The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer , 2008, Oncogene.

[9]  E. Surmacz,et al.  Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. , 2003, Oncogene.

[10]  J. Bartek,et al.  ATM Activation in Normal Human Tissues and Testicular Cancer , 2005, Cell cycle.

[11]  Dimitris Kletsas,et al.  Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions , 2005, Nature.

[12]  R. Blamey,et al.  Estrogen receptors and breast cancer. , 1981, Environmental health perspectives.

[13]  D. Ginzinger,et al.  The ATM gene is a target for epigenetic silencing in locally advanced breast cancer , 2004, Oncogene.

[14]  R. Gatti,et al.  ATM is down-regulated by N-Myc–regulated microRNA-421 , 2010, Proceedings of the National Academy of Sciences.

[15]  C. Klinge miRNAs and estrogen action , 2012, Trends in Endocrinology & Metabolism.

[16]  Y. Pommier,et al.  The CDK Subunit CKS2 Counteracts CKS1 to Control Cyclin A/CDK2 Activity in Maintaining Replicative Fidelity and Neurodevelopment , 2012, Developmental cell.

[17]  Xinbin Chen,et al.  p53, a Target of Estrogen Receptor (ER) α, Modulates DNA Damage-induced Growth Suppression in ER-positive Breast Cancer Cells* , 2012, The Journal of Biological Chemistry.

[18]  R. Strasser,et al.  Transcriptional activation of DNA-dependent protein kinase catalytic subunit gene expression by oestrogen receptor-α , 2010, EMBO reports.

[19]  Stephen T. C. Wong,et al.  Activation of the ATM-Snail pathway promotes breast cancer metastasis. , 2012, Journal of molecular cell biology.

[20]  Mark T. W. Ebbert,et al.  Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial , 2012, Clinical Cancer Research.

[21]  Paul Ellis,et al.  Dissecting the heterogeneity of triple-negative breast cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  E. Surmacz,et al.  Estrogen receptor-α regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells , 2003, Oncogene.

[23]  Wolfgang Heller,et al.  Triple-negative breast cancer: therapeutic options. , 2007, The Lancet. Oncology.

[24]  E. Alarid,et al.  Amping up estrogen receptors in breast cancer , 2007, Breast Cancer Research.

[25]  M. Dimopoulos,et al.  Differential Response of Immunohistochemically Defined Breast Cancer Subtypes to Anthracycline-Based Adjuvant Chemotherapy with or without Paclitaxel , 2012, PloS one.

[26]  J. Bartek,et al.  DNA Damage Response as an Anti-Cancer Barrier: Damage Threshold and the Concept of 'Conditional Haploinsufficiency' , 2007, Cell cycle.