Metabolic reprogramming of cancer cells allows for unregulated proliferation and metastasis. PCK1 and LPL are key players in breast cancer liver metastasis, thus acting as potential biomarkers and therapeutic targets (Bale et al., 2019). These enzymes allow metabolic adjustments, enhancing breast cancer cell survival in the liver microenvironment. In this essay, I discuss the metabolic roles of PCK1 and LPL in breast cancer liver metastasis and their role as biomarkers for diagnosis and prognosis.
The PCK1 gene encodes the cytosolic enzyme phosphoenolpyruvate carboxykinase 1, which is required to regulate gluconeogenesis and glyceroneogenesis. In liver metastases of breast cancer, the expression level of PCK1 is much higher than in primary tumors. This increased expression helps breast cancer cells thrive and proliferate in the liver microenvironment by improving gluconeogenesis and lipogenesis capabilities, which are reasonable for nutrient stress adaptation (Jiang et al., 2020). In particular, PCK1 promotes the synthesis of phospholipids, triglycerides, and cholesterol in metastatic cells. As a functional player, PCK1 significantly contributes to breast cancer cell adaptation and survival in the liver. It is a promising target for inhibiting metastasis formation and referring to particular metabolic needs that occur in metastatic breast cancer cells within this organ.
On the other hand, the LPL gene encodes for lipoprotein lipase, an enzyme essential in triglyceride hydrolysis within circulating lipoproteins. There is a meaningful increase in LPL expression in breast cancer cells that metastasize to the liver. This increased expression enables the metastatic breast cancer cells to obtain more fatty acids from the liver microenvironment, vital for maintaining their exponential division. The accumulated fatty acids are used for energy production through beta-oxidation or inserted into membranes to promote phospholipid synthesis. In addition, LPL accelerates hepatic metastasis via lipid signaling pathways, leading to cancer progression. The enhanced LPL expression supports metabolic and signaling functions in breast cancer cell survival within the liver, making it a key gene for breast cancer liver metastasis. The disruption mechanism of this particular process can be achieved by targeting LPL, which may also present an opportunity for the inhibition of metastatic outgrowth.
Recent research has revealed the potential for PCK1 and LPL to serve as novel biomarkers for breast cancer diagnosis and determining prognosis. PCK1 expression is upregulated in primary breast tumors compared to normal tissue, and its increased activity correlates with higher cancer stages and poorer prognosis. Elevated PCK1 increases glucose production through gluconeogenesis and enhanced lipogenesis, fueling rapid tumor growth’s biosynthetic and bioenergetic demands. Therefore, measuring PCK1 levels in biopsy samples could aid early breast cancer detection while also indicating aggressive disease. Similarly, increased tumor expression of LPL is associated with metastatic potential and worse clinical outcomes. LPL likely promotes metastasis by enhancing breast cancer cell scavenging of lipids from the microenvironment to support proliferation and survival. Notably, heightened LPL expression occurs in early-stage breast cancers destined for future metastasis. Hence, LPL levels could serve as a diagnostic biomarker, allowing prognosis by identifying tumors likely to spread (Yu et al., 2022). Since PCK1 and LPL influence key metabolic pathways hijacked by breast cancers, these enzymes are mechanistically relevant markers. Evaluating PCK1 and LPL expression levels or activity in patient samples could provide vital information for breast cancer diagnosis, prognosis, and making therapeutic decisions.
Both PCK1 and LPL enable key metabolic adaptations that allow breast cancer cells to metastasize and flourish in the liver. PCK1 promotes gluconeogenesis and lipogenesis, while LPL enhances lipid uptake. The upregulation of these enzymes correlates with aggressive disease and poor prognosis. As breast cancer rewires metabolism for growth and survival, enzymes like PCK1 and LPL represent promising biomarkers for diagnosis and determining outcomes. Evaluating PCK1 and LPL levels could provide critical insight into breast cancer progression and guide therapeutic decisions to impede metastasis.
References
Bale, R., Putzer, D., & Schullian, P. (2019). Local treatment of breast cancer liver metastasis. Cancers, 11(9), 1341. https://www.mdpi.com/2072-6694/11/9/1341/pdf
Jiang, H., Zhu, L., Xu, D., & Lu, Z. (2020). A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis. Cancer Communications, 40(9), 389-394. https://onlinelibrary.wiley.com/doi/pdf/10.1002/cac2.12084
Wang, L., Zhang, S., & Wang, X. (2021). The metabolic mechanisms of breast cancer metastasis. Frontiers in Oncology, 10, 602416. https://www.frontiersin.org/articles/10.3389/fonc.2020.602416/full
Yu, F., Pan, X. J., & Luo, J. (2022). Identification and Verification of Key Tumor Genes Associated with Diagnosis and Prognosis of Breast Cancer Based on Bioinformatics Analysis. Disease Markers, 2022. https://www.hindawi.com/journals/dm/2022/9041466/
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