The mTOR inhibitor rapamycin synergizes with a fatty acid synthase inhibitor to induce cytotoxicity in ER/HER2-positive breast cancer cells.

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.

• Authors: Chen Yan, Huang Wei, Zheng Minjuan, Xue Yan, Yang Jingyue, Liu Wenchao, Han Sheng
• Journal: PloS one (PLoS One) Vol. 9 Issue 5 Pg. e97697 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24866893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• Protein Kinase Inhibitors
• RNA, Messenger
• Cerulenin
• FASN protein, human
• Fatty Acid Synthase, Type I
• ERBB2 protein, human
• Receptor, ErbB-2
• Sirolimus

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cerulenin (pharmacology)
• Drug Synergism
• Estrogen Receptor alpha (genetics, metabolism)
• Fatty Acid Synthase, Type I (antagonists & inhibitors, genetics, 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, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sirolimus (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays