ASCT2 Regulates Fatty Acid Metabolism to Trigger Glutamine Addiction in Basal-like Breast Cancer.

Simple Summary: In recent years, cancer has gradually become a terrible killer of human health. Due to various factors such as tumor heterogeneity and the complexity of the microenvironment, completely conquering cancer has always been a major problem in the scientific research community. Therefore, more detailed research and individualized treatment are essential. Everyone knows that tumor cells in the process of rapid proliferation need replenishing nutrients to sustain their energy supply. Intervention of tumor cell metabolism is gradually becoming a way to treat cancer. As an important transporter of glutamine, ASCT2 can uptake glutamine from the tumor microenvironment to support the growth and metabolism of cancer cells. Deficiency of ASCT2 can significantly inhibit tumor progression. However, not all patients benefit from this treatment. Our study aims to explore the metabolic heterogeneity of breast cancer and its related mechanisms, as well as to find metabolic-sensitive populations for further precision treatment. As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine–lipid feedback loop. [ABSTRACT FROM AUTHOR]