Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase.
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.
Gutierrez
M Carolina
MC
Breast Center and Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
Detre
Simone
S
Johnston
Stephen
S
Mohsin
Syed K
SK
Shou
Jiang
J
Allred
D Craig
DC
Schiff
Rachel
R
Osborne
C Kent
CK
Dowsett
Mitch
M
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*
D018931:Antineoplastic Agents, Hormonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D048051:p38 Mitogen-Activated Protein Kinases