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

Int J Cancer. 2014 Sep 1;135(5):1257-63. doi: 10.1002/ijc.28769. Epub 2014 Feb 27.


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.

Keywords: PI3K/AKT/mTOR pathway; endocrine therapy, acquired hormone resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins
  • Chemotherapy, Adjuvant
  • Drug Resistance, Neoplasm*
  • Estrogen Antagonists / therapeutic use*
  • Estrogen Receptor alpha / antagonists & inhibitors*
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Metastasis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • TOR Serine-Threonine Kinases / metabolism


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents, Hormonal
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • ESR1 protein, human
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Phosphoproteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa