title: Modulation of tumor fatty acids, through overexpression or loss of thyroid hormone responsive protein spot 14 is associated with altered growth and metastasis.
abstract: BACKGROUND
  Spot14 (S14), encoded by the THRSP gene, regulates de novo fatty acid synthesis in the liver, adipose, and lactating mammary gland. We recently showed that S14 stimulated fatty acid synthase (FASN) activity in vitro, and increased the synthesis of fatty acids in mammary epithelial cells in vivo. Elevated de novo fatty acid synthesis is a distinguishing feature of many solid tumors compared with adjacent normal tissue. This characteristic is thought to be acquired during tumor progression, as rapidly proliferating cells have a heightened requirement for membrane phospholipids. Further, overexpression of FASN is sufficient to stimulate cell proliferation. While many studies have focused on the FASN enzyme in cancer biology, few studies have addressed the roles of proteins that modify FASN activity, such as S14.
  
  
  METHODS
  Tumor fatty acids were modulated using two mouse models, mouse mammary tumor virus (MMTV)-neu mice overexpressing S14 and MMTV-polyomavirus middle T antigen (PyMT) mice lacking S14, and associations between elevated or impaired fatty acid synthesis on tumor latency, growth, metastasis, and signaling pathways were investigated. We evaluated S14-dependent gene expression profiles in mouse tumors by microarray and used publicly available microarray datasets of human breast tumors.
  
  
  RESULTS
  S14 overexpression in the MMTV-Neu transgenic model is associated with elevated medium-chain fatty acids, increased proliferation and a shorter tumor latency, but reduced tumor metastasis compared to controls. Loss of S14 in the MMTV-PyMT model decreased FASN activity and the synthesis of medium-chain fatty acids but did not alter tumor latency. Impaired fatty acid synthesis was associated with reduced solid tumor cell proliferation, the formation of cystic lesions in some animals, and decreased phosphorylation of Src and protein kinase B (Akt). Analysis of gene expression in these mouse and human tumors revealed a relationship between S14 status and the expression of genes associated with luminal epithelial differentiation.
  
  
  CONCLUSIONS
  This study demonstrates a potential role for S14 in regulating mammary tumor growth and fatty acid synthesis in vivo. Furthermore, these results suggest that modulating the amount of medium chain fatty acids, by changing the levels of S14, has the potential to impact malignant mammary tumor phenotypes.
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Elizabeth.Wellberg@ucdenver.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wellberg
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Michael.Rudolph@ucdenver.edu.|Current Address: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Michael.Rudolph@ucdenver.edu.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Rudolph
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Andrew.Lewis@ucdenver.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lewis
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Nuria.Padillajust@ucdenver.edu.|Program in Cancer Biology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA. Nuria.Padillajust@ucdenver.edu.|Current Address: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Nuria.Padillajust@ucdenver.edu.
authors.forename: Nuria
authors.initials: N
authors.lastname: Padilla-Just
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Paul.Jedlicka@ucdenver.edu.|Program in Cancer Biology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA. Paul.Jedlicka@ucdenver.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA. Steve.Anderson@ucdenver.edu.|Program in Cancer Biology, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA. Steve.Anderson@ucdenver.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D005227:Fatty Acids; D009687:Nuclear Proteins; C501477:Thrsp protein, mouse; D014157:Transcription Factors; D064429:Fatty Acid Synthases