Bisphenol A stimulates the epithelial mesenchymal transition of estrogen negative breast cancer cells via FOXA1 signals

Arch Biochem Biophys. 2015 Nov 1;585:10-16. doi: 10.1016/j.abb.2015.09.006. Epub 2015 Sep 9.

Abstract

Estrogen receptor negative (ER-) breast cancer are associated with increased risks for metastasis and high rates of recurrence. Our present study revealed that nanomolar bisphenol A (BPA), a typical endocrine disrupting chemical, promoted the in vitro migration and induced mesenchymal transition (EMT) of ER-breast cancer cells. PCR array revealed that BPA can down regulate 12 and up regulate 2 genes involved in regulation of signal transduction and biological pathways of breast cancer. The down regulated genes included FOXA1, which is a key determinant of endocrine response and down regulated by BPA via a time dependent manner. Silencing of FOXA1 by siRNA triggered the EMT of SkBr3 cells. While over expression of FOXA1 abolished BPA induced EMT. Further, 10(-8) M BPA significantly increased the phosphorylation of ERK1/2, p38-MAPK, and Akt in SkBr3 cells, while only PI3K/Akt inhibitor LY294002 attenuated the BPA induced down regulation of FOXA1 and E-Cadherin (E-Cad). Over expression of Akt also suppressed FOXA1 expression in SkBr3 cells. It suggested that PI3K/Akt mediated, at least partially, BPA induced EMT of ER-breast cancer cells. In summary, our data provided the first evidence that BPA can promote the EMT of ER-breast cancer cells through down regulation of FOXA1.

Keywords: BPA; Breast cancer cells; EMT; FOXA1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzhydryl Compounds / pharmacology*
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chromones / pharmacology
  • Endocrine Disruptors / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / drug effects*
  • Estrogen Receptor alpha / deficiency
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hepatocyte Nuclear Factor 3-alpha / antagonists & inhibitors
  • Hepatocyte Nuclear Factor 3-alpha / genetics*
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Humans
  • Mammary Glands, Human / drug effects
  • Mammary Glands, Human / metabolism
  • Mammary Glands, Human / pathology
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Morpholines / pharmacology
  • Phenols / pharmacology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Benzhydryl Compounds
  • Cadherins
  • Chromones
  • Endocrine Disruptors
  • Enzyme Inhibitors
  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • Morpholines
  • Phenols
  • RNA, Small Interfering
  • estrogen receptor alpha, human
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • bisphenol A