Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase

J Clin Oncol. 2005 Apr 10;23(11):2469-76. doi: 10.1200/JCO.2005.01.172. Epub 2005 Mar 7.


Purpose: To evaluate growth factor receptor cross talk with the estrogen receptor (ER) in paired clinical breast cancer specimens and in a xenograft model before tamoxifen and at tumor progression as a possible mechanism for tamoxifen resistance.

Methods: Specimen pairs from 39 patients were tissue arrayed and stained for ER, progesterone receptor (PgR), Bcl-2, c-ErbB2 (HER-2), and phosphorylated (p) p38 mitogen-activated protein kinase (MAPK), p-ERK1/2 MAPK, and p-Akt. Xenograft MCF-7 tumors before and after tamoxifen resistance were assessed for levels of p-p38.

Results: Pretreatment, there were strong correlations between ER, PgR, and Bcl-2, and an inverse correlation between ER and HER-2. These correlations were lost in the tamoxifen- resistant tumors and replaced by strong correlations between ER and p-p38 and p-ERK. ER expression was lost in 17% of resistant tumors. Three (11%) of the 26 tumors originally negative for HER-2 became amplified and/or overexpressed at resistance. All ER-positive tumors that overexpressed HER-2 originally or at resistance expressed high levels of p-p38. In the pretreatment and tamoxifen-resistant specimens, there were strong correlations between p-p38 and p-ERK. In the tamoxifen-resistant xenograft tumors, like the clinical samples, there was a striking increase in p-p38.

Conclusion: The molecular pathways driving tumor growth can change as the tumor progresses. Crosstalk between ER, HER-2, p38, and ERK may contribute to tamoxifen resistance and may provide molecular targets to overcome this resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents, Hormonal / administration & dosage
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Biopsy
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / physiopathology*
  • Chemotherapy, Adjuvant
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Middle Aged
  • Receptor, ErbB-2 / physiology*
  • Receptors, Estrogen / drug effects*
  • Receptors, Estrogen / physiology*
  • Signal Transduction
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacology*
  • Tamoxifen / therapeutic use*
  • Transplantation, Heterologous
  • p38 Mitogen-Activated Protein Kinases / pharmacology*


  • Antineoplastic Agents, Hormonal
  • Receptors, Estrogen
  • Tamoxifen
  • Receptor, ErbB-2
  • p38 Mitogen-Activated Protein Kinases