Abstract | INTRODUCTION: METHODS: The effects of GW9662 and exogenously added palmitate on breast cells (BT474, MDA-MB-361, MCF-7, and human mammary epithelial cells) in monolayer culture were assessed. Mass spectrometric quantitation of fatty acids and fluorescence-based high content microscopy assays of cell growth, apoptosis, triglyceride storage and reactive oxygen species production were used. RESULTS: ERBB2-positive breast cancer cells are more sensitive to inhibition of PPARgamma activity by the antagonist GW9662. PPARgamma inhibition results in increased levels of total fats in the cells, mostly because of increased amounts of palmitic and stearic unsaturated acids. Administration of exogenous palmitate is lethal to ERBB2-positive but not to ERBB2-negative cells. GW9662 exacerbates the effects of palmitate addition on BT474 and MDA-MB-361 cells, but it has no significant effect on MCF-7 and human mammary epithelial cells. Palmitate administration results in a fivefold to tenfold greater increase in fat stores in ERBB2-negative cells compared with ERBB2-positive cells, which suggests that the ERBB2-positive cells have maximized their ability to store fats and that additional palmitate is toxic to these cells. Both PPARgamma inhibition and palmitate administration result in increased reactive oxygen species production in BT474 cells. The cell death that results from this treatment can be counteracted by the antioxidant N-acetyl cysteine. CONCLUSIONS: Our findings indicate that PPARgamma activity enables ERBB2-positive breast cancer cells, which produce high levels of fat, to convert fatty acids to triglycerides, allowing these cells to avert the cell death that results from lipotoxicity. Endogenous palmitate toxicity represents a genetically based property of ERBB2-positive breast cancer that can be exploited for therapeutic intervention.
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Authors | Antonis Kourtidis, Rekha Srinivasaiah, Richard D Carkner, M Julia Brosnan, Douglas S Conklin |
Journal | Breast cancer research : BCR
(Breast Cancer Res)
Vol. 11
Issue 2
Pg. R16
( 2009)
ISSN: 1465-542X [Electronic] England |
PMID | 19298655
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- PPAR gamma
- Palmitates
- RNA, Messenger
- Reactive Oxygen Species
- Receptor, ErbB-2
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Topics |
- Apoptosis
(drug effects)
- Breast Neoplasms
(metabolism, pathology)
- Cell Proliferation
(drug effects)
- Fluorescent Antibody Technique
- Humans
- PPAR gamma
(metabolism)
- Palmitates
(pharmacology)
- RNA, Messenger
(genetics, metabolism)
- Reactive Oxygen Species
(metabolism)
- Receptor, ErbB-2
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
(drug effects)
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