title: Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Breast Center and Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M Carolina
authors.initials: MC
authors.lastname: Gutierrez
authors.forename: Simone
authors.initials: S
authors.lastname: Detre
authors.forename: Stephen
authors.initials: S
authors.lastname: Johnston
authors.forename: Syed K
authors.initials: SK
authors.lastname: Mohsin
authors.forename: Jiang
authors.initials: J
authors.lastname: Shou
authors.forename: D Craig
authors.initials: DC
authors.lastname: Allred
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D048051:p38 Mitogen-Activated Protein Kinases / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D048051:p38 Mitogen-Activated Protein Kinases