title: mTOR inhibition in breast cancer: unraveling the complex mechanisms of mTOR signal transduction and its clinical implications in therapy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Emory University School of Medicine, Winship Cancer Institute, Department of Hematology and Medical Oncology, 1365 Clifton Road, Atlanta, GA 30322, USA. roregan@emory.edu
authors.forename: Ruth
authors.initials: R
authors.lastname: O'Regan
authors.forename: Natalyn Nicole
authors.initials: NN
authors.lastname: Hawk
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human