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    Shc Signaling Proteins: Prognostic and Predictive Markers in Breast Cancer

    Scientific Abstract:
    Title: Shc signaling proteins: prognostic and predictive markers in breast cancer Background: Shc signaling proteins are implicated in many pathways associated with aggressive cancers, and many breast cancer cell lines derived from highly aggressive tumors contain high levels of activated, tyrosine phosphorylated (PY)-Shc relative to protein levels of an inhibitory 66-kDa Shc isoform. By semi-quantitative immunohistochemical (IHC) assay, we recently determined the levels of PY-Shc and p66 Shc in primary tumors from 116 breast cancer patients, and reported that PY-Shc and p66 Shc, especially when expressed as the ratio of PY-Shc to p66 Shc, were very strong prognostic markers (relative risk >10, P<0.005) for relapse and for death in patients with node negative, as well as in patients with more advanced, node positive disease. The Shc Ratio’s prognostic value was independent of all clinical markers when tested in Cox proportional hazards models. Further analysis suggested that high PY-Shc levels preferentially identified patients who relapse but then do well with subsequent interventions, while low p66 Shc levels preferentially identified patients who relapse and then succumb to their disease. Objectives: 1. To validate the Shc Ratio as an independent prognostic indicator in breast cancer. 2. To test the hypothesis that high levels of PY-Shc predict relapse with good outcome, while low levels of p66 Shc predict relapse with poor outcome. Specific Aims: 1. To validate the Shc Ratio as an independent prognostic indicator for relapse-free and disease-specific survival in [Aim 1.1] node negative breast cancer; [Aim 1.2] node-positive breast cancer; Aim 2. Analyze relapse-free survival and disease-specific survival as functions of PY-Shc, p66 Shc and . Study Design: PY-Shc and p66 Shc levels will be determined by semi-quantitative immunohistochemical analysis of archival breast tumor specimens, with raters blinded to clinical characteristics and patient outcomes. An first level of rigor for these Aims will be accomplished using blinded specimens obtained from the Cooperative Breast Cancer Tissue Resource directed by the NCI. The prognostic value of PY-Shc, p66 Shc, and the Shc Ratio will be analyzed as continuous variables in Cox proportional hazards models, and will be compared for interactions with various clinical and molecular markers by likelihood ratio analysis. Cutpoint-categorized Shc variables will be examined in both univariate log-rank models and Cox models. Validation of our initial findings will be used to justify a more rigorous test of these hypotheses using archival specimens from well-controlled clinical trials such as NSABP B-06. Potential Outcomes and Benefits of the Research: Rigorous validation of the prognostic and predictive value of PY-Shc, p66 Shc and the Shc Ratio in primary tumors as described here would constitute a level-of-evidence 2 to 3 for these marker proteins and would be an important and critical step towards their clinical use. These molecular markers, especially in combination with other markers such as uPA/PA-1, should identify women at low risk of recurrent disease who do not need adjuvant therapy, women whose disease will respond to adjuvant therapy, and women who will likely fail current adjuvant therapies.

    Lay Abstract:
    Title: Shc signaling proteins: prognostic and predictive markers in breast cancer Background: Currently available clinical markers do not accurately identify women with breast cancer who will and will not benefit from adjuvant therapy. Shc signaling proteins are implicated in many pathways associated with aggressive cancers, and many breast cancer cell lines derived from highly aggressive tumors contain high levels of activated, tyrosine phosphorylated (PY)-Shc relative to protein levels of an inhibitory 66-kDa Shc isoform. In a recent pilot study, we reported that the levels of PY-Shc and p66 Shc, especially when expressed as the ratio of PY-Shc to p66 Shc, were very strong prognostic markers for relapse and for death in patients with node negative, as well as in patients with more advanced, node positive disease. The Shc Ratio’s prognostic value was independent of all clinical markers. Further analysis suggested that high PY-Shc levels preferentially identified patients who relapse but then do well with subsequent interventions, while low p66 Shc levels preferentially identified patients who relapse and then succumb to their disease. The objectives of the work proposed here will be to rigorously validate the Shc proteins as independent prognostic markers, both in patients with node negative and in patients with node positive disease, and further to determine if high levels of PY-Shc predict relapse with good outcome, while low levels of p66 Shc predict relapse with poor outcome. These studies will be conducted at two levels of rigor: the first will make use of archival breast tissues banked in the Cooperative Breast Cancer Tissue Resource directed by the NCI; affirmation of our hypotheses at the first level will then justify using the precious specimens from well-controlled clinical trials. Potential Benefits of the Research: Rigorous validation of the prognostic and predictive value of the Shc proteins would be an important and critical step towards their clinical use. These molecular markers, especially in combination with other clinical and molecular markers, should identify women at low risk of recurrent disease who do not need adjuvant therapy, women whose disease will respond to adjuvant therapy, and women who will likely fail current adjuvant therapies.