Abstract 1417: Stimulation of fatty acid synthesis by Spot14 enhances tumor cell proliferation but decreases metastasis in vivo

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA We have recently observed that Spot14 (S14), also known as Thyroid Hormone Responsive Protein, stimulates de novo fatty acid biosynthesis in mammary epithelial cells by increasing Fatty Acid Synthase (FASN) activity. In the presence of S14, FASN had increased Vmax, decreased Km, and shifted product formation toward medium chain fatty acids. Numerous studies have suggested that high expression of FASN is associated with higher tumor grade and poor clinical outcome, and likewise elevated expression of S14 has been linked to a poor clinical outcome for patients with invasive disease. In contrast, our analysis of S14 expression in databases of human breast tumors representing a variety of stages, grades, and subtypes suggests that high S14 is associated with ER-positive status, the luminal intrinsic subtype, and consequently, a favorable patient outcome. To determine the effect of S14 on mammary tumorigenesis in vivo, we crossed S14 null mice to MMTV-PyMT mice. Tumor latency was not altered in mice lacking S14; however, tumor cell proliferation was significantly decreased. Tumors arising in MMTV-PyMT mice lacking S14 were less dense and had a cystic morphology. There was a decrease in the phosphorylation of Src at Y416 and Akt at S473, indicating that activation of both signaling molecules was decreased in tumors lacking S14. Furthermore, tumors lacking S14 had reduced levels of de novo synthesized fatty acids. We also crossed MMTV-S14 transgenic mice expressing S14 in the mammary epithelium, to MMTV-Neu line 202 mice and observed that S14 overexpression significantly shortened tumor latency, increased tumor cell proliferation and increased concentration of fatty acids in tumor cells. Despite the increased proliferative index observed in the MMTV-Neu tumors expressing S14, there was a decrease in metastatic lesions detected in the lungs compared to MMTV-Neu mice. Gene expression profiling of mouse tumors revealed that tumors overexpressing S14 displayed features of lobular differentiation including increased expression of Elf5, a proposed master regulator of mammary differentiation, and expression of milk protein genes. Elevated fatty acid synthesis is a distinguishing feature of many solid tumors compared to adjacent normal tissue and this activity is thought to be acquired during tumor progression, as rapidly proliferating cancer cells have a heightened requirement for membrane phospholipid precursors. Our studies suggest that increased de novo fatty acid biosynthesis is sufficient to stimulate tumor cell proliferation; however, this is not correlated with increased metastasis, and in fact, tumors that expressed high levels of S14 appeared to have a more differentiated phenotype that may correlate with improved clinical outcome. Citation Format: Elizabeth A. Wellberg, Michael C. Rudolph, Andrew Lewis, Steven M. Anderson. Stimulation of fatty acid synthesis by Spot14 enhances tumor cell proliferation but decreases metastasis in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1417. doi:10.1158/1538-7445.AM2014-1417