Abstract
Estrogens induce breast tumor cell proliferation by directly regulating gene expression via the estrogen receptor (ER) transcriptional activity and by affecting growth factor signaling pathways such as mitogen-activated protein kinase (MAPK) and AKT/mammalian target of rapamycin Complex1 (mTORC1) cascades. In this study we demonstrated the preclinical therapeutic efficacy of combining the aromatase inhibitor letrozole with the multi-kinase inhibitor sorafenib in aromatase-expressing breast cancer cell lines. Treatment with letrozole reduced testosterone-driven cell proliferation, by inhibiting the synthesis of estrogens. Sorafenib inhibited cell proliferation in a concentration-dependent manner; this effect was not dependent on sorafenib-mediated inhibition of Raf1, but involved the down-regulation of mTORC1 and its targets p70S6K and 4E-binding protein 1 (4E-BP1). At concentrations of 5-10 μM the growth-inhibitory effect of sorafenib was associated with the induction of apoptosis, as indicated by release of cytochrome c and Apoptosis-Inducing Factor into the cytosol, activation of caspase-9 and caspase-7, and PARP-1 cleavage. Combination of letrozole and sorafenib produced a synergistic inhibition of cell proliferation associated with an enhanced accumulation of cells in the G(0)/G(1) phase of the cell cycle and with a down-regulation of the cell cycle regulatory proteins c-myc, cyclin D1, and phospho-Rb. In addition, longer experiments (12 weeks) demonstrated that sorafenib may be effective in preventing the acquisition of resistance towards letrozole. Together, these results indicate that combination of letrozole and sorafenib might constitute a promising approach to the treatment of hormone-dependent breast cancer.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / metabolism
-
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
-
Apoptosis / drug effects
-
Apoptosis Inducing Factor / metabolism
-
Aromatase / genetics
-
Aromatase / metabolism
-
Aromatase Inhibitors / pharmacology
-
Benzenesulfonates / pharmacology
-
Breast Neoplasms / enzymology
-
Breast Neoplasms / genetics
-
Breast Neoplasms / pathology*
-
Caspase 7 / metabolism
-
Caspase 9 / metabolism
-
Cell Cycle / drug effects
-
Cell Cycle Proteins
-
Cell Line, Tumor
-
Cell Proliferation / drug effects*
-
Cyclin D1 / metabolism
-
Cytochromes c / metabolism
-
Dose-Response Relationship, Drug
-
Drug Resistance, Neoplasm
-
Drug Synergism
-
Estradiol / metabolism
-
Female
-
Humans
-
Letrozole
-
Mechanistic Target of Rapamycin Complex 1
-
Multiprotein Complexes
-
Niacinamide / analogs & derivatives
-
Nitriles / pharmacology
-
Phenylurea Compounds
-
Phosphoproteins / metabolism
-
Phosphorylation
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerases / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
Proteins / metabolism
-
Proto-Oncogene Proteins c-myc / metabolism
-
Pyridines / pharmacology
-
Retinoblastoma Protein / metabolism
-
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
-
Sorafenib
-
TOR Serine-Threonine Kinases
-
Testosterone / metabolism
-
Time Factors
-
Transfection
-
Triazoles / pharmacology
Substances
-
AIFM1 protein, human
-
Adaptor Proteins, Signal Transducing
-
Apoptosis Inducing Factor
-
Aromatase Inhibitors
-
Benzenesulfonates
-
CCND1 protein, human
-
Cell Cycle Proteins
-
EIF4EBP1 protein, human
-
MYC protein, human
-
Multiprotein Complexes
-
Nitriles
-
Phenylurea Compounds
-
Phosphoproteins
-
Protein Kinase Inhibitors
-
Proteins
-
Proto-Oncogene Proteins c-myc
-
Pyridines
-
Retinoblastoma Protein
-
Triazoles
-
Cyclin D1
-
Niacinamide
-
Testosterone
-
Estradiol
-
Letrozole
-
Cytochromes c
-
Sorafenib
-
Aromatase
-
PARP1 protein, human
-
Poly (ADP-Ribose) Polymerase-1
-
Poly(ADP-ribose) Polymerases
-
Mechanistic Target of Rapamycin Complex 1
-
Ribosomal Protein S6 Kinases, 70-kDa
-
TOR Serine-Threonine Kinases
-
CASP7 protein, human
-
CASP9 protein, human
-
Caspase 7
-
Caspase 9