Phytoestrogens induce apoptosis via extrinsic pathway, inhibiting nuclear factor-kappaB signaling in HER2-overexpressing breast cancer cells

Anticancer Res. 2011 Oct;31(10):3301-13.

Abstract

Background: Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are largely unknown. This study aimed to examine the effect of genistein and quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells.

Materials and methods: The antiproliferative effects of phytoestrogens were tested by proliferation assays. Flow cytometry was performed to analyze the cell cycle. The effect of phytoestrogens on cell-signaling molecules was determined by Western blotting.

Results: Genistein and quercetin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of subG(0)/G(1) apoptotic fractions. Genistein and quercetin induced extrinsic apoptosis pathway, up-regulating p53. Genistein and quercetin reduced the phosphorylation level of IκBα, and abrogated the nuclear translocation of p65 and its phosphorylation within the nucleus.

Conclusion: Genistein and quercetin exert their antiproliferative activity by inhibiting NFκB signaling. Phytoestrogens could be potential useful compounds to prevent or treat HER2-overexpressing breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Genistein / pharmacology
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • NF-kappa B / metabolism*
  • Phosphorylation / drug effects
  • Phytoestrogens / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quercetin / pharmacology
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction / drug effects*
  • Tumor Suppressor Protein p53 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p16
  • NF-kappa B
  • Phytoestrogens
  • Tumor Suppressor Protein p53
  • Quercetin
  • Genistein
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases