Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

Cancer Lett. 2012 Oct 1;323(1):77-87. doi: 10.1016/j.canlet.2012.03.034. Epub 2012 Apr 3.


Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / physiology*
  • Everolimus
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Immunosuppressive Agents / pharmacology
  • Letrozole
  • Neoadjuvant Therapy
  • Nitriles / therapeutic use*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism
  • Triazoles / therapeutic use*


  • Antineoplastic Agents
  • Imidazoles
  • Immunosuppressive Agents
  • Nitriles
  • Quinolines
  • Triazoles
  • Letrozole
  • Everolimus
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • dactolisib
  • Sirolimus