Abstract 2845: The role of PSAT1 in triple negative breast cancer metastasis

Abstract

Abstract Breast cancer is the number one diagnosed cancer type among women in the United States (NCI). This disease can be stratified into different molecular subtypes, including triple negative breast cancer (TNBC), each of which can have different therapeutic options, patient prognosis, and survival outcomes. TNBC disease readily metastasizes and different processes have been implicated in the development of metastatic disease. The serine synthesis pathway (SSP) is responsible for de novo production of serine and consists of three enzymes, including phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). PSAT1 catalyzes the second step in this pathway, is elevated in more aggressive tumor types such as basal breast cancer (Pollari, 2011) and has clinically been associated with poorer distant metastatic free survival and overall survival (unpublished from KMPlotter) in breast cancer patients. These prior studies combined with our own preliminary data underscores the hypothesis that PSAT1 promotes the metastatic potential of triple negative breast cancer. This hypothesis was first evaluated through immunohistochemistry examination of patient samples which demonstrated that expression of PSAT1 increases with TNBC tumor grade. In vitro assays of proliferation showed no difference upon loss of PSAT1, however, metastasis (migration and invasion) was significantly inhibited upon PSAT1 suppression. In a tail-vein experimental metastasis model, suppression of PSAT1 significantly inhibited the formation of tumor nodules. Mechanistically, the relevance for de novo serine synthesis pathway was examined in vitro via suppression of PHGDH. Decreased PHGDH did not affect proliferation or the metastatic capability of either cell line. Further, addition of exogenous serine could not rescue metastatic deficiencies upon loss of PSAT1. Our results suggest that PSAT1 does contribute to metastasis in TNBC and that this affect appears to be independent of its metabolic role in serine synthesis. While studies are ongoing, this points to the potential of a non-canonical function of PSAT1 being a therapeutic target for patients with TNBC that are currently lacking treatments options. Citation Format: Stephanie Metcalf, Traci Kruer, Susan Dougherty, Rumeysa Biyik-Sit, Carolyn Klinge, Brian Clem. The role of PSAT1 in triple negative breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2845.