PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy |
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| Authors: | Karin Beelen Laurien D.C. Hoefnagel Mark Opdam Jelle Wesseling J. Sanders Andrew D. Vincent Paul J. van Diest Sabine C. Linn |
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| Affiliation: | 1. Department of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;2. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;3. Department of Pathology, University Medical Center Utrecht, The Netherlands;4. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;5. Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, The Netherlands |
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| Abstract: | Both preclinical and clinical data suggest that activation of the PI3K/AKT/mTOR pathway in response to hormonal therapy results in acquired endocrine therapy resistance. We evaluated differences in activation of the PI3K/AKT/mTOR pathway in estrogen receptor α (ERα) positive primary and corresponding metastatic breast cancer tissues using immunohistochemistry for downstream activated proteins, like phosphorylated mTOR (p‐mTOR), phosphorylated 4E Binding Protein 1 (p‐4EBP1) and phosphorylated p70S6K (p‐p70S6K). For p‐mTOR and p‐4EBP1, the proportion of immunostained tumor cells (0–100%) was scored. Cytoplasmic intensity (0–3) was assessed for p‐p70S6K. The difference between expression of these activated PI3K/AKT/mTOR proteins‐ in primary and metastatic tumor was calculated and tested for an association with adjuvant endocrine therapy. In patients who had received endocrine therapy (N = 34), p‐mTOR expression increased in metastatic tumor lesions compared to the primary tumor (median difference 45%), while in patients who had not received adjuvant endocrine therapy (N = 37), no difference was found. Similar results were observed for p‐4EBP1 and p‐p70S6K expression. In multivariate analyses, adjuvant endocrine therapy was significantly associated with an increase in p‐mTOR (p = 0.01), p‐4EBP1 (p = 0.03) and p‐p70S6K (p = 0.001), indicating that compensatory activation of the PI3K/AKT/mTOR pathway might indeed be a clinically relevant resistance mechanism resulting in acquired endocrine therapy resistance. |
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| Keywords: | PI3K/AKT/mTOR pathway endocrine therapy, acquired hormone resistance |
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