PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy

Karin Beelen, Laurien D.C. Hoefnagel, Mark Opdam, Jelle Wesseling, J. Sanders, Andrew D. Vincent, Paul J. Van Diest, Sabine C. Linn

Research output: Contribution to journalArticle

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. What's new? Inhibitors of the PI3K/AKT/mTOR pathway can overcome the resistance to estrogen-depletion therapy that often develops in metastatic breast cancer. In this study, the authors compared primary and metastatic tumors; their results suggest that activation of the PI3K/AKT/mTOR pathway in patients who receive adjuvant endocrine therapy is a clinically relevant mechanism of acquired hormone resistance. For identification of companion diagnostics for PI3K/AKT/mTOR inhibitors, the authors conclude that analyzing primary tumor tissue may often fail to predict treatment response in metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)1257-1263
Number of pages7
JournalInternational Journal of Cancer
Volume135
Issue number5
DOIs
StatePublished - Sep 1 2014

Keywords

  • PI3K/AKT/mTOR pathway
  • endocrine therapy acquired hormone resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Beelen, K., Hoefnagel, L. D. C., Opdam, M., Wesseling, J., Sanders, J., Vincent, A. D., Van Diest, P. J., & Linn, S. C. (2014). PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy. International Journal of Cancer, 135(5), 1257-1263. https://doi.org/10.1002/ijc.28769