1. The mTOR inhibitor rapamycin synergizes with a fatty acid synthase inhibitor to induce cytotoxicity in ER/HER2-positive breast cancer cells.
- Author
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Yan C, Wei H, Minjuan Z, Yan X, Jingyue Y, Wenchao L, and Sheng H
- Subjects
- Animals, Apoptosis drug effects, Blotting, Western, Breast Neoplasms enzymology, Cell Movement drug effects, Cell Proliferation drug effects, Cerulenin pharmacology, Estrogen Receptor alpha genetics, Fatty Acid Synthase, Type I genetics, Fatty Acid Synthase, Type I metabolism, Female, Fluorescent Antibody Technique, Indirect, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, Mice, Nude, Protein Kinase Inhibitors pharmacology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptor, ErbB-2 genetics, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Drug Synergism, Estrogen Receptor alpha metabolism, Fatty Acid Synthase, Type I antagonists & inhibitors, Receptor, ErbB-2 metabolism, Sirolimus pharmacology
- Abstract
Patients with ER/HER2-positive breast cancer have a poor prognosis and are less responsive to selective estrogen receptor modulators; this is presumably due to the crosstalk between ER and HER2. Fatty acid synthase (FASN) is essential for the survival and maintenance of the malignant phenotype of breast cancer cells. An intimate relationship exists between FASN, ER and HER2. We hypothesized that FASN may be the downstream effector underlying ER/HER2 crosstalk through the PI3K/AKT/mTOR pathway in ER/HER2-positive breast cancer. The present study implicated the PI3K/AKT/mTOR pathway in the regulation of FASN expression in ER/HER2-positive breast cancer cells and demonstrated that rapamycin, an mTOR inhibitor, inhibited FASN expression. Cerulenin, a FASN inhibitor, synergized with rapamycin to induce apoptosis and inhibit cell migration and tumorigenesis in ER/HER2-positive breast cancer cells. Our findings suggest that inhibiting the mTOR-FASN axis is a promising new strategy for treating ER/HER2-positive breast cancer.
- Published
- 2014
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