Phthalates induce proliferation and invasiveness of estrogen receptor-negative breast cancer through the AhR/HDAC6/c-Myc signaling pathway

FASEB J. 2012 Feb;26(2):778-87. doi: 10.1096/fj.11-191742. Epub 2011 Nov 2.


The environmentally present group of chemical phthalates, or phthalate esters, has been recognized as a rising threat to public health, including cancer. While most studies have addressed the estrogenic effects of phthalates in malignancies of the breast and the prostate, little is known about their role in the etiology of hormone-independent cancer. Here we show that treatments with the phthalates n-butyl benzyl phthalate (BBP) and dibutyl phthalate (DBP) at 1 μM induced proliferation (BBP, 3.2-fold; DBP, 3.2-fold), migration (BBP, 2.6-fold; DBP, 2.6-fold), invasion (BBP, 2.7-fold; DBP, 3.1-fold), and tumor formation (EC(50): BBP, 0.12 μM; DBP, 0.22 μM) in estrogen receptor (ER)-negative breast cancer cells (MDA-MB-231). We further demonstrate that phthalates stimulated the cell surface aryl hydrocarbon receptor (AhR) and triggered the downstream cyclic AMP (cAMP)-PKA-CREB1 signaling cascade. The pathway led to increased expression of HDAC6, which facilitated nuclear assembly of the β-catenin-LEF1/TCF4 transcriptional complex and transactivation of the c-Myc oncogene. This nongenomic pathway emanated from the phthalate-induced AhR promoted tumorigenesis of ER-negative breast cancer. Collectively, our findings revealed a novel oncogenic mechanism of phthalates in breast cancer independent from their estrogenic activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / etiology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinogens / toxicity
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Histone Deacetylase 6
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Neoplasm Invasiveness
  • Phthalic Acids / toxicity*
  • Plasticizers / toxicity
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects


  • Carcinogens
  • MYC protein, human
  • Phthalic Acids
  • Plasticizers
  • Proto-Oncogene Proteins c-myc
  • Receptors, Aryl Hydrocarbon
  • Receptors, Estrogen
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases