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Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis
Chandan Kumar-Sinha1, Kathleen Woods Ignatoski, Marc E Lippman
1Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Abstract:
HER2 (erbB2/neu) is a member of the erbB family of receptor tyrosine kinases and is involved in regulating the growth of several types of human carcinomas. HER2 represents a successful therapeutic target of the biotechnology era as exemplified by the drug Herceptin (trastuzumab), which has clinical activity in a subset of breast cancer patients. Using DNA microarrays, we identified a cohort of genes that are differentially regulated by HER2 in breast epithelial cells. One of the HER2-regulated genes discovered was fatty acid synthase (FAS), which has been shown to be overexpressed in breast cancer as well as other cancers. FAS is implicated in tumorigenesis through its role in cell proliferation and membrane lipid incorporation of neoplastic cells. Here, we demonstrate that HER2-mediated induction of FAS is inhibitable by Herceptin and tyrosine kinase inhibitors of HER2. Through a phosphatidylinositol 3'-kinase-dependent pathway, HER2 stimulates the FAS promoter and ultimately mediates increased fatty acid synthesis. Interestingly, pharmacological inhibition of FAS preferentially induced apoptosis of HER2-overexpressing breast epithelial cells relative to matched vector control cells. These studies characterize a molecular connection between two genes individually implicated in tumorigenesis but never linked together.
Insights
This study reveals that the drug Herceptin can inhibit the HER2-mediated overexpression of fatty acid synthase (FAS) in breast cancer cells. Inhibiting FAS also selectively triggers cancer cell death, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- HER2 (erbB2/neu) is a receptor tyrosine kinase crucial for human carcinoma growth.
- Herceptin (trastuzumab) is a targeted therapy effective in a subset of breast cancer patients with HER2.
- Fatty acid synthase (FAS) is overexpressed in various cancers, including breast cancer, and linked to tumorigenesis.
Purpose of the Study:
- To identify genes regulated by HER2 in breast epithelial cells.
- To investigate the molecular link between HER2 and fatty acid synthase (FAS).
- To evaluate the therapeutic potential of targeting the HER2-FAS pathway.
Main Methods:
- DNA microarrays were used to identify HER2-regulated genes.
- Investigated the effect of Herceptin and HER2 tyrosine kinase inhibitors on FAS expression.
- Utilized phosphatidylinositol 3'-kinase (PI3K) pathway analysis.
- Assessed the impact of pharmacological FAS inhibition on cell apoptosis.
Main Results:
- HER2 differentially regulates a cohort of genes in breast epithelial cells, including fatty acid synthase (FAS).
- HER2-mediated induction of FAS is inhibited by Herceptin and HER2 tyrosine kinase inhibitors.
- HER2 stimulates the FAS promoter via a PI3K-dependent pathway, increasing fatty acid synthesis.
- Pharmacological inhibition of FAS selectively induces apoptosis in HER2-overexpressing breast cancer cells.
Conclusions:
- Establishes a molecular connection between HER2 and FAS in breast tumorigenesis.
- Demonstrates that the HER2-FAS pathway is a potential therapeutic target.
- Suggests that targeting FAS could be a viable strategy for treating HER2-positive breast cancers.