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

Chen Yan; Huang Wei; Zheng Minjuan; Xue Yan; Yang Jingyue; Liu Wenchao; Han Sheng

doi:10.1371/journal.pone.0097697

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

PLoS One. 2014 May 27;9(5):e97697. doi: 10.1371/journal.pone.0097697. eCollection 2014.

Authors

Chen Yan¹, Huang Wei², Zheng Minjuan³, Xue Yan¹, Yang Jingyue¹, Liu Wenchao¹, Han Sheng⁴

Affiliations

¹ Department of Oncology, Xi'jing Hospital, Fourth Military Medical University, Xi'an, PR China.
² Department of Cardiology, Xi'jing hospital, Fourth military medical university, Xi'an, PR China.
³ Department of Ultrasound, Xi'jing Hospital, Fourth Military Medical University, Xi'an, PR China.
⁴ State Key Laboratory of Military Stomatology, Department of Information Center, School of Stomatology, Fourth Military Medical University, Xi'an, PR China.

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.

Publication types

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

MeSH terms

Animals
Apoptosis / drug effects
Blotting, Western
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / pathology*
Cell Movement / drug effects
Cell Proliferation / drug effects
Cerulenin / pharmacology
Drug Synergism*
Estrogen Receptor alpha / genetics
Estrogen Receptor alpha / metabolism*
Fatty Acid Synthase, Type I / antagonists & inhibitors*
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
Receptor, ErbB-2 / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Sirolimus / pharmacology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

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

Grants and funding

Funding provided by National Natural Science Foundation of China (81001180); Natural Science Foundation of Shaanxi Province, China (2010JM4005, 2013K12-03-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.