Abstract P1-01-15: Investigation of phosphoserine aminotransferase 1 and its role in breast cancer progression

Abstract

Abstract Metastasis and endocrine resistance are two factors that complicate therapeutic intervention in breast cancer patients and lead to poorer overall survival. Metastasis is known to be responsible for 90% of cancer related deaths, and is especially prevalent in triple negative breast cancer (TNBC); while endocrine resistance can affect up to 50% of patients diagnosed with estrogen receptor positive breast cancer (ER+BC). Phosphoserine aminotransferase 1 (PSAT1) catalyzes the second step within de novo serine biosynthesis and increased expression of enzymes in this pathway have been linked to progression of breast cancer and poor clinical outcomes. Within our preliminary retrospective analysis of human breast cancer patients, we identified an inverse association with elevated transcript levels and poorer distant metastasis free survival, which, coupled to a previously reported correlation of PSAT1 with response to endocrine therapy in patients with ER+BC, we postulate that PSAT1 contributes to breast cancer progression through promotion of metastasis and/or endocrine resistance. To initially determine relevance for PSAT1, immunohistochemistry was performed to determine PSAT1 expression in human breast cancer patients. We found that PSAT1 expression is increased through breast cancer progression, with highest levels observed within metastatic conditions. To investigate the metastatic contribution of PSAT1, we silenced PSAT1 expression within the triple negative breast cancer cell line (TNBC), MDA-MB-231. While suppression of PSAT1 had no effect on proliferation, there was a significant decrease in the motility and invasion of these cells. In addition, decreased PSAT1 substantially inhibited lung metastasis following tail-vein injections of MDA-MB-231 cells in vivo. To investigate PSAT1's role in endocrine resistance, we used parental MCF-7 cells and an endocrine-resistant derivative cell line (LY2) and found that LY2-resistant cells exhibited higher PSAT1 expression compared to parental MCF-7 cells. Lastly, suppression of PSAT1 was able to sensitize the LY2 cells to 4-hydroxytamoxifen treatment. Taken together, these data indicate that PSAT1 may contribute to the progression of human breast cancer via either metastasis or endocrine resistance or both and could potentially serve as a viable target for new therapies. Citation Format: Metcalf S, Kruer T, Klinge C, Clem B. Investigation of phosphoserine aminotransferase 1 and its role in breast cancer progression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-15.