Co-targeting ER and HER family receptors induces apoptosis in HER2-normal or overexpressing breast cancer models

Anticancer Res. 2015 Mar;35(3):1243-50.

Abstract

Background: Estrogen receptor (ER) and human epidermal growth factor receptor (HER) family receptors interact in breast cancer; co-targeting these receptors is of interest. We previously reported on a synergistic growth inhibition for the combination of trastuzumab plus tamoxifen in HER2+/ER+ BT474 cells, but no induction of apoptosis. Herein we describe the effects of co-targeting in models of differing HER2 overexpression status (MCF7 HER2-normal/ER+, BT474 HER2-overexpressing/ER+).

Materials and methods: Assays of proliferation were carried-out using WST-1, cell cycle using flow cytometry, and apoptosis by determination of sub-G1 population and by annexin-V.

Results: Combining a dual HER2/EGFR kinase inhibitor with anti-estrogens induces apoptosis of BT474 cells. Furthermore, in MCF7 cells, despite HER2-normal status and lack of response to single-agent HER2 inhibitors, addition of HER2 inhibitors or dual HER2/EGFR inhibitor to anti-estrogens augments the antiproliferative effect of anti-estrogens, and converts the drug effect from cytostatic to apoptosis-inducing.

Conclusion: ER-HER co-targeting enhanced the antitumor effects and can bring about effects of targeting HER2 in models of HER2-normal breast cancer.

Keywords: Breast cancer; EGFR; GW2974; HER2; apoptosis; estrogen receptor (ER); fulvestrant (Faslodex); proliferation; tamoxifen; trastuzumab (Herceptin).

Publication types

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

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Apoptosis / drug effects*
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Estrogen Antagonists / administration & dosage*
  • Female
  • Humans
  • Receptor, ErbB-2 / analysis
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Receptors, Estrogen / analysis
  • Tamoxifen / administration & dosage
  • Trastuzumab

Substances

  • Antibodies, Monoclonal, Humanized
  • Estrogen Antagonists
  • Receptors, Estrogen
  • Tamoxifen
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab