Regulation of Mammary Tumor Formation and Lipid Biosynthesis by Spot14.

摘要

Spot14 (S14), encoded by the THRSP gene, regulates de novo fatty acid synthesis in the liver, adipose, and lactating mammary gland. S14 has recently been shown to stimulate FASN activity, increasing the synthesis of medium chain fatty acids in mammary epithelial cells in vivo. Elevated de novo fatty acid synthesis is a distinguishing feature of many solid tumors compared to adjacent normal tissue. This characteristic is thought to be acquired during tumor progression, as rapidly proliferating cancer cells have a heightened requirement for membrane phospholipids. Further, overexpression of fatty acid synthase (FASN) in vivo was 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. Synthesis of de novo fatty acids was modulated using two mouse models, MMTV-Neu mice overexpressing S14 and MMTV-PyMT mice lacking S14, and effects of activated or impaired fatty acid synthesis on tumor latency, growth, metastasis, and signal transduction were investigated. We evaluated S14-dependent gene expression profiles in these mouse models by microarray and used publicly available microarray datasets of human breast tumors. Here, we show that S14 overexpression in the MMTV-Neu transgenic model stimulated medium-chain fatty acid synthesis, increased proliferation and shortened tumor latency, but reduced tumor metastasis. Loss of S14 in the MMTV-PyMT model was associated with reduced levels 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 Akt. Analysis of gene expression in these mouse models and human tumors revealed a relationship between S14 status and the expression of genes associated with luminal epithelial differentiation.