Lani
02-18-2010, 08:32 PM
and ensures its own survival ...such additional knowledge carries with it the possibility of discovering its Achilles heel. Interestingly, most of the study was done on BT474, an ER+her2+ breast cancer cell line(most studies either use SKBr3, an ER- her2+ cell line or a her2- ER+ cell line MCF7 transfected with her2 (ie, her2 gene injected in using gene therapy = an artificial construct). Dr. Javier Menendez, who was not involved with this particular research, has been saying for years that inhibitors of fatty acid synthesis are very effectively syngergistic w herceptin and has spotlighted in many of his papers the abnormal fat metabolism of her2+ breast cancers (even citing synergism of xenical AKA Alii with herceptin in the lab---but Alii is not absorbed by people, which is how it works!)
Cancer Res. 2010 Feb 16. [Epub ahead of print]
An RNA Interference Screen Identifies Metabolic Regulators NR1D1 and PBP as Novel Survival Factors for Breast Cancer Cells with the ERBB2 Signature.
Kourtidis A, Jain R, Carkner RD, Eifert C, Brosnan MJ, Conklin DS.
Authors' Affiliations: Department of Biomedical Sciences, Cancer Research Center, University at Albany, Rensselaer, New York; Ordway Research Institute, Albany, New York.
Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers; however, therapies targeting this gene have not proved to be as effective as was initially hoped. Transcriptional profiling meta-analyses have shown that there are approximately 150 genes co-overexpressed with ERBB2, suggesting that these genes may represent alternative factors influencing ERBB2-positive tumors. Here we describe an RNA interference-based analysis of these genes that identifies transcriptional regulators of fat synthesis and storage as being critical for the survival of these cells. These transcription factors, nuclear receptor subfamily 1, group D, member 1 (NR1D1) and peroxisome proliferator activated receptor gamma binding protein (PBP), both reside on ERBB2-containing 17q12-21 amplicons and are part of the ERBB2 expression signature. We show that NR1D1 and PBP act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. Malate dehydrogenase 1 and malic enzyme 1, enzymes that link glycolysis and fatty acid synthesis, are also regulated by NR1D1. The resulting high-level fat production from increased expression of these genes likely contributes to an abnormal cellular energy metabolism based on aerobic glycolysis. Together, these results show that the cells of this aggressive form of breast cancer are genetically preprogrammed to depend on NR1D1 and PBP for the energy production necessary for survival. Cancer Res; 70(5); 1783-92.
PMID: 20160030
Cancer Res. 2010 Feb 16. [Epub ahead of print]
An RNA Interference Screen Identifies Metabolic Regulators NR1D1 and PBP as Novel Survival Factors for Breast Cancer Cells with the ERBB2 Signature.
Kourtidis A, Jain R, Carkner RD, Eifert C, Brosnan MJ, Conklin DS.
Authors' Affiliations: Department of Biomedical Sciences, Cancer Research Center, University at Albany, Rensselaer, New York; Ordway Research Institute, Albany, New York.
Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers; however, therapies targeting this gene have not proved to be as effective as was initially hoped. Transcriptional profiling meta-analyses have shown that there are approximately 150 genes co-overexpressed with ERBB2, suggesting that these genes may represent alternative factors influencing ERBB2-positive tumors. Here we describe an RNA interference-based analysis of these genes that identifies transcriptional regulators of fat synthesis and storage as being critical for the survival of these cells. These transcription factors, nuclear receptor subfamily 1, group D, member 1 (NR1D1) and peroxisome proliferator activated receptor gamma binding protein (PBP), both reside on ERBB2-containing 17q12-21 amplicons and are part of the ERBB2 expression signature. We show that NR1D1 and PBP act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. Malate dehydrogenase 1 and malic enzyme 1, enzymes that link glycolysis and fatty acid synthesis, are also regulated by NR1D1. The resulting high-level fat production from increased expression of these genes likely contributes to an abnormal cellular energy metabolism based on aerobic glycolysis. Together, these results show that the cells of this aggressive form of breast cancer are genetically preprogrammed to depend on NR1D1 and PBP for the energy production necessary for survival. Cancer Res; 70(5); 1783-92.
PMID: 20160030