Abstract 5417: PHGDH expression level impacts tumorigenesis and metastasis in human breast cancer

Abstract

Abstract Background: Phosphoglycerate dehydrogenase (PHGDH) is a metabolic enzyme, which is associated with the first step of serine synthesis. The gene encoding this enzyme is often elevated in some types of human cancer, including breast cancer. There are some researches that High-PHGDH expression promotes cancer cell proliferation and tumorigenesis. However, latest study showed that although breast tumors with high expression levels of PHGDH had more possibility to undergo primary-tumor growth, were less likely to metastasize than tumors with low expression of PHGDH by using mouse cell derived mouse models and PDX models. Nevertheless, the applicability of these outcomes to human breast cancer cell lines remains uncertain. Methods: The survival analysis according to PHGDH mRNA expression was analyzed in METABRIC datasets of breast cancer and the whole-transcriptome sequencing data of 120 breast cancer patients. To investigate the effect of PHGDH in human TNBC cell lines, PHGDH overexpressing MDA-MB-231 cell lines and PHGDH knockdown MDA-MB-468 cell lines were established. Subsequent functional experiments were performed to explore the influence of PHGDH on breast cancer tumorigenesis and metastasis. Results: In the analysis using METABRIC datasets, overall survival and disease-free survival were reduced in patients with high PHGDH expression and basal type breast cancer showed the highest mRNA level of PHGDH. Using whole-transcriptome sequencing data of 120 breast cancer patients, we also found PHGDH expression level was higher in cancer tissue(n=120) than normal tissue(n=90). In particular, triple-negative breast cancer indicated higher PHGDH level than luminal type breast cancer. We also used this data to perform analysis of overall survival, disease-free survival, metastasis free survival of non-TNBC patient and it resulted in reducing survival rate when patient showed high-PHGDH expression. However, TNBC patients demonstrated diametrical results in the identical analysis. We examined the impact of PHGDH overexpression in MDA-MB-231 cells and PHGDH knockdown in MDA-MB-468 cells, observing increased proliferation and decreased migration in breast cancer cells with elevated PHGDH levels. Conversely, PHGDH knockdown exhibited opposing effects. Subsequently analysis of markers associated with epithelial-mesenchymal transition revealed a correlation with PHGDH expression. Conclusions: Our data suggest that a potential role for PHGDH in breast cancer as a marker of reduced survival in triple-negative breast cancer, and as a regulator of cancer cell proliferation and metastasis. Citation Format: Jihong Baik, Juhee Kim, Sangeun Lee, Ayoung Park, Kyoungseob Shin, Sunghoon Kwon, Hanbyoel Lee, Wonshik Han. PHGDH expression level impacts tumorigenesis and metastasis in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5417.