Estrogen receptor α mediates proliferation of breast cancer MCF-7 cells via a p21/PCNA/E2F1-dependent pathway

FEBS J. 2014 Feb;281(3):927-42. doi: 10.1111/febs.12658. Epub 2014 Jan 2.

Abstract

High expression of estrogen receptor α (ERα) is associated with a poor prognosis that correlates closely with cellular proliferation in breast cancer. However, the exact molecular mechanism by which ERα controls breast cancer cell proliferation is not clear. Here we report that ERα regulates the cell cycle by suppressing p53/p21 and up-regulating proliferating cell nuclear antigen (PCNA) and proliferation-related Ki-67 antigen (Ki-67) to promote proliferation of MCF-7 cells. In addition, 17-β-estradiol (E2) enhances ERα-induced proliferation of MCF-7 cells by stimulating expression of PCNA and Ki-67. Knockdown of ERα significantly affects PCNA/Ki-67 and p53/p21 expression. Furthermore, ERα inhibits the transcriptional activity of p53/p21 in an estrogen response element-dependent manner. More importantly, we provide new evidence that ERα mediates proliferation of MCF-7 cells by up-regulating miR-17 to silence the expression of p21. Thus, these data provide new insights into the underlying effect of ERα on breast cancer proliferation.

Keywords: MCF-7 cell proliferation; PCNA; estrogen receptor α (ERα); miR-17; p21.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Cycle
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism*
  • Estradiol / metabolism
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor alpha / antagonists & inhibitors
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Ki-67 Antigen / biosynthesis
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism
  • MCF-7 Cells
  • MicroRNAs / biosynthesis
  • MicroRNAs / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Response Elements
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Estrogen Receptor alpha
  • Ki-67 Antigen
  • MIRN17 microRNA, human
  • MicroRNAs
  • Neoplasm Proteins
  • Proliferating Cell Nuclear Antigen
  • Recombinant Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • estrogen receptor alpha, human
  • Estradiol