Session: FP16-Cancers of Endocrine Organs: Mechanisms of Tumorigenesis & Progression
Room 206 (Moscone Center)
Poster Board SUN-295
Elizabeth A. Wellberg, Michael C. Rudolph, Andrew Lewis, and Steven M. Anderson.
Department of Pathology, UC Denver-Anschutz Medical Campus, Aurora, Colorado 80045
Spot14 (S14), which is encoded by the THRSP gene, regulates fatty acid synthesis in the liver, adipose, and lactating mammary gland, and has been linked to breast cancer cell growth, differentiation, and 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 a favorable patient outcome. To determine the effect of S14 on mammary tumorigenesis in vivo, we created transgenic mice expressing S14 in the mammary epithelium, and demonstrate that S14 modulates Neu-driven mammary tumorigenesis. Elevated S14 significantly shortened tumor latency in MMTV-Neu mice, and stimulated both fatty acid synthesis and proliferation. Moreover, S14 loss in MMTV-PyMT tumors reduced cell proliferation. Despite the direct relationship between S14 and tumor growth in vivo, S14 overexpression in Neu-induced mammary tumors resulted in decreased tumor metastasis, which is consistent with the reduced metastasis observed in patients with breast tumors expressing high levels of S14. Furthermore, gene expression profiling of mouse tumors revealed a link between S14 expression and features of lobular differentiation including elevated Elf5, a proposed master regulator gene of mammary gland differentiation. Elevated 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 phospholipid precursors; however, studies suggest that overexpression of fatty acid synthase is sufficient to stimulate cell proliferation. While the link between fatty acid synthesis and cancer cell growth and survival is well established, it is not clear if increasing fatty acid synthesis promotes cancer metastasis. In the mammary epithelium, elevated fatty acid synthesis is associated with lactogenic differentiation. We suggest that in the presence of prolactin during lactation, high S14 stimulates fatty acid synthesis, which supports milk production and lactation. In the presence of oncogenic stimuli such as that provided by Neu, S14-mediated fatty acid synthesis promotes the expansion of these relatively well differentiated cells, resulting in reduced metastasis.
The authors have nothing to disclose.
Nothing to Disclose: EAW, MCR, ASL, SMA
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