mTOR inhibition in breast cancer: unraveling the complex mechanisms of mTOR signal transduction and its clinical implications in therapy

Expert Opin Ther Targets. 2011 Jul;15(7):859-72. doi: 10.1517/14728222.2011.575362. Epub 2011 Apr 8.

Abstract

Introduction: The mammalian target of rapamycin (mTOR)/PI3K/Akt pathway is altered in breast cancer cells, as demonstrated by mutations in both the upstream and downstream regulators of mTOR, including phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss or Akt/PI3K activation, and potentially in the mTOR protein itself. This contributes to increased cell proliferation, as well as growth-factor independence and endocrine resistance. Thus, mTOR inhibition holds considerable promise as a rational therapeutic strategy in breast cancer.

Areas covered: This review describes how dysregulation of the mTOR pathway in breast cancer may contribute to breast cancer pathogenesis, as well as discussing preclinical and clinical data that support mTOR inhibitor therapy.

Expert opinion: Direct blockade of the mTOR pathway is a new and intriguing area in breast cancer therapy, with the potential to modulate growth-factor and estrogen-dependent and -independent pathways, that contribute to the pathogenesis and progression of breast tumors. mTOR inhibitors demonstrate significant biologic activity with manageable toxicities, in combination with hormonal therapy and chemotherapy, in both the neoadjuvant and metastatic breast cancer settings.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / metabolism
  • Female
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt