Regulation of Mammary Tumorigenesis and Lipid Biosynthesis by Spot 14.

摘要

THRSP/Spot14 regulates de novo fatty acid synthesis in the lactating mammary gland and has also been correlated with a poor patient outcome for women with breast cancer. Despite this correlation, studies have not been done to causatively link Spot14 with breast tumorigenesis. We hypothesized that Spot14 overexpression in mammary epithelial cells that express the Neu oncogene would elevate de novo fatty acid synthesis, resulting in tumor formation, growth, and metastasis. To address this hypothesis, we generated transgenic mice expressing Neu and Spot14 (Neu/S14) in the mammary gland and compared them to Neu controls. Neu/S14 mice develop tumors with a shorter latency and with a higher proliferative index than Neu controls. The tumors, however, are not metastatic. Gene expression profiling revealed an increase in the levels of genes associated with lactation in the Neu/S14 tumors. GC-mas s spectrometry and NMR metabolite studies showed that Neu/S14 tumors have higher lactose and fatty acid levels than Neu tumors. Overexpression of Spot14 in cultured mammary epithelial cells stimulated proliferation but did not stimulate differentiation. We propose a model that predicts Spot14 is expressed in differentiated cells in the mammary epithelium, and that it can stimulate cell proliferation in the presence of oncogenic signaling. These studies indicate that Spot14 might be an important marker of a well-differentiated tumor that is not likely to metastasize.