Expression Of Serine Synthetic Enzymes Alters The Sensitivity Of Er-Positive Breast Cancer Cells To Tamoxifen

Estrogen receptor positive breast cancer (ER+BC) is the most common form of breast cancer accounting for 65-75% of all diagnoses, yet, due to the availability of targeted therapies, has the best overall survival outcomes. However, it is estimated that up to 30% of all patients develop resistance to these therapies, resulting in recurrence or disease progression. Phosphoserine aminotransferase 1 (PSAT1), which is an enzyme within the serine synthetic pathway (SSP), has previously been implicated in endocrine resistance. Therefore, we sought to determine if there was a functional correlation between expression of PSAT1 or other serine synthetic enzymes and sensitivity to 4-hydroxytamoxifen (4-OHT) treatment. To investigate the correlation between PSAT1, another SSP enzyme phosphoglycerate dehydrogenase (PHGDH), and endocrine resistance, we examined clinical data from ER+ patients who received tamoxifen as their sole endocrine therapy. Using two separate cohorts, we confirmed that higher PSAT1 and PHDGH expression negatively correlates with poorer outcomes in tamoxifen treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis are elevated in tamoxifen resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of both PSAT1 or PHGDH in each cell type. While overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition, conversely, silencing of PSAT or PHGDH resulted in decreased proliferation in tamoxifen-resistant LCC9 treated with 4-OHT. Taken together, we postulate that overexpression of SSP enzymes appear to contribute to tamoxifen resistance in ER+BC and indicate a potential combinatorial therapeutic option. Citation Format: Stephanie Metcalf, Traci Kruer, Susan Dougherty, James L. Wittliff, Carolyn M. Klinge, Brian F. Clem. Expression of serine synthetic enzymes alters the sensitivity of ER-positive breast cancer cells to tamoxifen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3734.