ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer

Cancer Discov. 2011 Sep;1(4):338-51. doi: 10.1158/2159-8290.CD-11-0101. Epub 2011 Jul 20.

Abstract

Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER(+) xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.

Keywords: CDK4; Estrogen receptor; aromatase inhibitor; breast; resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / therapy
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • E2F Transcription Factors / genetics*
  • E2F Transcription Factors / metabolism*
  • Estrogen Receptor Modulators / pharmacology
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / deficiency*
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Female
  • Gene Expression
  • Humans
  • Mice
  • Mice, Nude
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Transcription, Genetic

Substances

  • E2F Transcription Factors
  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Estrogens
  • Phosphatidylinositol 3-Kinases
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4