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
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Breast Neoplasms
70-kDa Ribosomal Protein S6 Kinases
Carrier Proteins
Therapeutics
Neoplasms
TOR Serine-Threonine Kinases
Estrogen Receptors
Estrogens
Multivariate Analysis
Immunohistochemistry
Hormones

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Beelen, K., Hoefnagel, L. D. C., Opdam, M., Wesseling, J., Sanders, J., Vincent, A. D., ... 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

PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy. / Beelen, Karin; Hoefnagel, Laurien D C; Opdam, Mark; Wesseling, Jelle; Sanders, J.; Vincent, Andrew D.; Van Diest, Paul J.; Linn, Sabine C.

In: International Journal of Cancer, Vol. 135, No. 5, 01.09.2014, p. 1257-1263.

Research output: Contribution to journalArticle

Beelen, K, Hoefnagel, LDC, Opdam, M, Wesseling, J, Sanders, J, Vincent, AD, Van Diest, PJ & Linn, SC 2014, 'PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy', International Journal of Cancer, vol. 135, no. 5, pp. 1257-1263. https://doi.org/10.1002/ijc.28769
Beelen, Karin ; Hoefnagel, Laurien D C ; Opdam, Mark ; Wesseling, Jelle ; Sanders, J. ; Vincent, Andrew D. ; Van Diest, Paul J. ; Linn, Sabine C. / PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy. In: International Journal of Cancer. 2014 ; Vol. 135, No. 5. pp. 1257-1263.
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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. 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.",
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