Targeting Hypoxia and HIF1α in Triple-Negative Breast Cancer: New Insights from Gene Expression Profiling and Implications for Therapy.

Simple Summary: Breast cancer is a leading cause of death among women worldwide, with aggressive subtypes such as triple-negative breast cancer posing a significant challenge. These cancers are often resistant to treatment and have a poor prognosis. Our research focused on understanding the role of hypoxia in the development and progression of triple-negative breast cancer. We studied the effects of hypoxia on MDA-MB-231 cells, a model for triple-negative breast cancer. Using cobalt chloride (CoCl2) to mimic the effects of hypoxia, we observed changes in cell behavior and gene expression. We found that hypoxia promotes the migration and survival of MDA-MB-231 cells, increasing their aggressiveness and resistance to treatment through the activation of hypoxia-inducible factor 1α. Our findings suggest that targeting hypoxia-related pathways could be a promising strategy for developing new therapies for triple-negative breast cancer. By understanding how hypoxia contributes to the aggressive nature of these cancers, we can develop more effective treatments that will improve patient outcomes. This research contributes to the development of new and more effective treatments for aggressive breast cancer. By targeting hypoxia, we aim to improve the survival rates and quality of life of patients with this devastating disease. Breast cancer is a complex and multifaceted disease with diverse risk factors, types, and treatment options. Triple-negative breast cancer (TNBC), which lacks the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is the most aggressive subtype. Hypoxia is a common feature of tumors and is associated with poor prognosis. Hypoxia can promote tumor growth, invasion, and metastasis by stimulating the production of growth factors, inducing angiogenesis, and suppressing antitumor immune responses. In this study, we used mRNA-seq technology to systematically investigate the gene expression profile of MDA-MB-231 cells under hypoxia. We found that the hypoxia-inducible factor (HIF) signaling pathway is the primary pathway involved in the cellular response to hypoxia. The genes in which expression levels were upregulated in response to hypoxia were regulated mainly by HIF1α. In addition, hypoxia upregulated various genes, including Nim1k, Rimkla, Cpne6, Tpbgl, Kiaa11755, Pla2g4d, and Ism2, suggesting that it regulates cellular processes beyond angiogenesis, metabolism, and known processes. We also found that HIF1α was hyperactivated in MDA-MB-231 cells under normoxia. A HIF1α inhibitor effectively inhibited the invasion, migration, proliferation, and metabolism of MDA-MB-231 cells. Our findings suggest that hypoxia and the HIF signaling pathway play more complex and multifaceted roles in TNBC than previously thought. These findings have important implications for the development of new therapeutic strategies for TNBC. [ABSTRACT FROM AUTHOR]