p66 Shc and tyrosine-phosphorylated Shc in primary breast tumors identify patients likely to relapse despite tamoxifen therapy.
BACKGROUND
Shc adapter proteins are secondary messenger proteins involved in various cellular pathways, including those mediating receptor tyrosine kinase signaling and apoptosis in response to stress. We have previously reported that high levels of tyrosine-phosphorylated Shc (PY-Shc) and low levels of its inhibitory p66 Shc isoform are strongly prognostic for identifying both early node-negative and more advanced, node-positive, primary breast cancers with high risk for recurrence. Because aberrant activation of tyrosine kinases upstream of Shc signaling proteins has been implicated in resistance to tamoxifen--the most widely prescribed drug for treatment of estrogen receptor-positive breast cancer--we hypothesized that Shc isoforms may identify patients at increased risk of relapsing despite tamoxifen treatment.


METHODS
Immunohistochemical analyses of PY-Shc and p66 Shc were performed on archival primary breast cancer tumors from a population-based cohort (60 patients, 9 relapses) and, for validation, an independent external cohort (31 patients, 13 relapses) in which all patients received tamoxifen as a sole systemic adjuvant prior to relapse.


RESULTS
By univariate and multivariate analyses, the Shc proteins were very strong and independent predictors of treatment failure in both the population-based cohort (interquartile hazard ratio = 8.3, 95% confidence interval [CI] 1.8 to 38, P = 0.007) and the validating cohort (interquartile relative risk = 12.1, 95% CI 1.7 to 86, P = 0.013).


CONCLUSIONS
These results suggest that the levels of PY-Shc and p66 Shc proteins in primary tumors identify patients at high risk for relapsing despite treatment with tamoxifen and therefore with further validation may be useful in guiding clinicians to select alternative adjuvant treatment strategies.
Frackelton
A Raymond
AR
Department of Research, Roger Williams Medical Center, 825 Chalkstone Avenue, Providence, RI 02908, USA. A_Frackelton_Jr@brown.edu
Lu
Li
L
Davol
Pamela A
PA
Bagdasaryan
Robert
R
Hafer
Laurie J
LJ
Sgroi
Dennis C
DC
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D020033:Protein Isoforms; D011960:Receptors, Estrogen; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013629:Tamoxifen / Q000627:therapeutic use*; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D010750:Phosphoproteins; D020033:Protein Isoforms; D011960:Receptors, Estrogen; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013629:Tamoxifen; D014443:Tyrosine