Ras/Raf-1/MAPK pathway mediates response to tamoxifen but not chemotherapy in breast cancer patients.
OBJECTIVE
The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in the development and progression of cancer, and may influence response to treatments such as tamoxifen and chemotherapy. In this study we investigated whether the expression and activation of the key components of this pathway influenced clinical outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women with breast cancer.


METHODS
Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 [pRaf(ser338) and pRaf(ser259), respectively], MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and overall survival.


RESULTS
Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy. Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses. Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen treatment (P=0.03).


CONCLUSIONS
This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies pRaf(ser338) as a potential marker of resistance to estrogen receptor-targeted therapy. In addition, it suggests that expression of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the addition of chemotherapy may be of benefit.
McGlynn
Liane M
LM
Endocrine Cancer Group, Division of Cancer Studies and Molecular Pathology, University Department of Surgery, Glasgow Royal Infirmary, Glasgow, United Kingdom.
Kirkegaard
Tove
T
Edwards
Joanne
J
Tovey
Sian
S
Cameron
David
D
Twelves
Chris
C
Bartlett
John M S
JM
Cooke
Timothy G
TG
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008875:Middle Aged; D011379:Prognosis; D019908:Proto-Oncogene Proteins c-raf / Q000032:analysis / Q000502:physiology*; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000627:therapeutic use*; D018631:ras Proteins / Q000032:analysis / Q000502:physiology*
D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins