S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth.
Most breast cancers exhibit brisk lipogenesis, and require it for growth. S14 is a lipogenesis-related nuclear protein that is overexpressed in most breast cancers. Sterol response element-binding protein-1c (SREBP-1c) is required for induction of lipogenesis-related genes, including S14 and fatty acid synthase (FAS), in hepatocytes, and correlation of SREBP-1c and FAS expression suggested that SREBP-1c drives lipogenesis in tumors as well. We directly tested the hypothesis that SREBP-1c drives S14 expression and mediates lipogenic effects of progestin in T47D breast cancer cells. Dominant-negative SREBP-1c inhibited induction of S14 and FAS mRNAs by progestin, while active SREBP-1c induced without hormone and superinduced in its presence. Changes in S14 mRNA were reflected in protein levels. A lag time and lack of progestin response elements indicated that S14 and FAS gene activation by progestin is indirect. Knockdown of S14 reduced, whereas overexpression stimulated, T47D cell growth, while nonlipogenic MCF10a mammary epithelial cells were not growth-inhibited. These data directly demonstrate that SREBP-1c drives S14 gene expression in breast cancer cells, and progestin magnifies that effect via an indirect mechanism. This supports the prediction, based on S14 gene amplification and overexpression in breast tumors, that S14 augments breast cancer cell growth and survival.
Martel
Peter M
PM
Department of Medicine, Division of Endocrinology, Dartmouth Medical School, Lebanon.
Bingham
Chad M
CM
McGraw
Charles J
CJ
Baker
Christina L
CL
Morganelli
Peter M
PM
Meng
Marie Louise
ML
Armstrong
Jessica M
JM
Moncur
Joel T
JT
Kinlaw
William B
WB
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D064429:Fatty Acid Synthases; D005784:Gene Amplification; D005786:Gene Expression Regulation / Q000187:drug effects*; D005799:Genes, Dominant; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011372:Progestins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020218:Response Elements; D051780:Sterol Regulatory Element Binding Protein 1 / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D011372:Progestins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; C051065:THRSP protein, human; D014157:Transcription Factors; D019014:fas Receptor; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D064429:Fatty Acid Synthases