A MicroRNA196a2* and TP63 Circuit Regulated by Estrogen Receptor-α and ERK2 that Controls Breast Cancer Proliferation and Invasiveness Properties

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Abstract

Estrogen receptor α (ERα) is present in about 70 % of human breast cancers and, working in conjunction with extracellular signal-regulated kinase 2 (ERK2), this nuclear hormone receptor regulates the expression of many protein-encoding genes. Given the crucial roles of miRNAs in cancer biology, we investigated the regulation of miRNAs by estradiol (E2) through ERα and ERK2, and their impact on target gene expression and phenotypic properties of breast cancer cells. We identified miRNA-encoding genes harboring overlapping ERα and ERK chromatin binding sites in ERα-positive MCF-7 cells and showed ERα and ERK2 to bind to these sites and to be required for transcriptional induction of these miRNAs by E2. Hsa-miR-196a2*, the most highly estrogen up-regulated miRNA, markedly down-regulated tumor protein p63 (TP63), a member of the p53 family. In ERα-positive and ERα-negative breast cancer cells, proliferative and invasiveness properties were suppressed by hsa-miR-196a2* expression and enhanced by hsa-miR-196a2* antagonism or TP63 target protector oligonucleotides. Hsa-miR-196a2* and TP63 were inversely correlated in breast cancer cell lines and in a large cohort of human breast tumors, implying clinical relevance. The findings reveal a tumor suppressive role of hsa-miR-196a2* through regulation of TP63 by ERα and/or ERK2 signaling. Manipulating the hsa-miR-196a2*-TP63 axis might provide a potential tumor-suppressive strategy to alleviate the aggressive behavior and poor prognosis of some ERα-positive as well as many ERα-negative breast cancers.

Original languageEnglish (US)
Pages (from-to)78-91
Number of pages14
JournalHormones and Cancer
Volume4
Issue number2
DOIs
StatePublished - Jan 1 2013

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Mitogen-Activated Protein Kinase 1
Estrogen Receptors
Breast Neoplasms
MicroRNAs
Neoplasms
Proteins
Overlapping Genes
MCF-7 Cells
Cytoplasmic and Nuclear Receptors
Oligonucleotides
Chromatin
Estradiol
Estrogens
Binding Sites
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cancer Research

Cite this

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title = "A MicroRNA196a2* and TP63 Circuit Regulated by Estrogen Receptor-α and ERK2 that Controls Breast Cancer Proliferation and Invasiveness Properties",
abstract = "Estrogen receptor α (ERα) is present in about 70 {\%} of human breast cancers and, working in conjunction with extracellular signal-regulated kinase 2 (ERK2), this nuclear hormone receptor regulates the expression of many protein-encoding genes. Given the crucial roles of miRNAs in cancer biology, we investigated the regulation of miRNAs by estradiol (E2) through ERα and ERK2, and their impact on target gene expression and phenotypic properties of breast cancer cells. We identified miRNA-encoding genes harboring overlapping ERα and ERK chromatin binding sites in ERα-positive MCF-7 cells and showed ERα and ERK2 to bind to these sites and to be required for transcriptional induction of these miRNAs by E2. Hsa-miR-196a2*, the most highly estrogen up-regulated miRNA, markedly down-regulated tumor protein p63 (TP63), a member of the p53 family. In ERα-positive and ERα-negative breast cancer cells, proliferative and invasiveness properties were suppressed by hsa-miR-196a2* expression and enhanced by hsa-miR-196a2* antagonism or TP63 target protector oligonucleotides. Hsa-miR-196a2* and TP63 were inversely correlated in breast cancer cell lines and in a large cohort of human breast tumors, implying clinical relevance. The findings reveal a tumor suppressive role of hsa-miR-196a2* through regulation of TP63 by ERα and/or ERK2 signaling. Manipulating the hsa-miR-196a2*-TP63 axis might provide a potential tumor-suppressive strategy to alleviate the aggressive behavior and poor prognosis of some ERα-positive as well as many ERα-negative breast cancers.",
author = "Kyuri Kim and Zeynep Madak-Erdogan and Rosa Ventrella and Katzenellenbogen, {Benita S}",
year = "2013",
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doi = "10.1007/s12672-012-0129-3",
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T1 - A MicroRNA196a2* and TP63 Circuit Regulated by Estrogen Receptor-α and ERK2 that Controls Breast Cancer Proliferation and Invasiveness Properties

AU - Kim, Kyuri

AU - Madak-Erdogan, Zeynep

AU - Ventrella, Rosa

AU - Katzenellenbogen, Benita S

PY - 2013/1/1

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N2 - Estrogen receptor α (ERα) is present in about 70 % of human breast cancers and, working in conjunction with extracellular signal-regulated kinase 2 (ERK2), this nuclear hormone receptor regulates the expression of many protein-encoding genes. Given the crucial roles of miRNAs in cancer biology, we investigated the regulation of miRNAs by estradiol (E2) through ERα and ERK2, and their impact on target gene expression and phenotypic properties of breast cancer cells. We identified miRNA-encoding genes harboring overlapping ERα and ERK chromatin binding sites in ERα-positive MCF-7 cells and showed ERα and ERK2 to bind to these sites and to be required for transcriptional induction of these miRNAs by E2. Hsa-miR-196a2*, the most highly estrogen up-regulated miRNA, markedly down-regulated tumor protein p63 (TP63), a member of the p53 family. In ERα-positive and ERα-negative breast cancer cells, proliferative and invasiveness properties were suppressed by hsa-miR-196a2* expression and enhanced by hsa-miR-196a2* antagonism or TP63 target protector oligonucleotides. Hsa-miR-196a2* and TP63 were inversely correlated in breast cancer cell lines and in a large cohort of human breast tumors, implying clinical relevance. The findings reveal a tumor suppressive role of hsa-miR-196a2* through regulation of TP63 by ERα and/or ERK2 signaling. Manipulating the hsa-miR-196a2*-TP63 axis might provide a potential tumor-suppressive strategy to alleviate the aggressive behavior and poor prognosis of some ERα-positive as well as many ERα-negative breast cancers.

AB - Estrogen receptor α (ERα) is present in about 70 % of human breast cancers and, working in conjunction with extracellular signal-regulated kinase 2 (ERK2), this nuclear hormone receptor regulates the expression of many protein-encoding genes. Given the crucial roles of miRNAs in cancer biology, we investigated the regulation of miRNAs by estradiol (E2) through ERα and ERK2, and their impact on target gene expression and phenotypic properties of breast cancer cells. We identified miRNA-encoding genes harboring overlapping ERα and ERK chromatin binding sites in ERα-positive MCF-7 cells and showed ERα and ERK2 to bind to these sites and to be required for transcriptional induction of these miRNAs by E2. Hsa-miR-196a2*, the most highly estrogen up-regulated miRNA, markedly down-regulated tumor protein p63 (TP63), a member of the p53 family. In ERα-positive and ERα-negative breast cancer cells, proliferative and invasiveness properties were suppressed by hsa-miR-196a2* expression and enhanced by hsa-miR-196a2* antagonism or TP63 target protector oligonucleotides. Hsa-miR-196a2* and TP63 were inversely correlated in breast cancer cell lines and in a large cohort of human breast tumors, implying clinical relevance. The findings reveal a tumor suppressive role of hsa-miR-196a2* through regulation of TP63 by ERα and/or ERK2 signaling. Manipulating the hsa-miR-196a2*-TP63 axis might provide a potential tumor-suppressive strategy to alleviate the aggressive behavior and poor prognosis of some ERα-positive as well as many ERα-negative breast cancers.

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