Purinergic and GABAergic signaling in metastatic triple-negative breast cancer cells

• Grant number: 25/04884-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2025
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Claudiana Lameu
• Grantee: Beatriz da Silva Luiz Cavalcanti
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Breast cancer is the most common cancer among women, accounting for 15.5% of female cancer deaths. The triple negative subtype (TNBC) is highly aggressive and is associated with a worse prognosis. Brain metastasis is one of the main causes of death from the disease and studies indicate that the acquisition of a phenotype similar to GABAergic neurons facilitates colonization in the brain. Our group revealed increased expression of GABAergic genes, such as ABAT and GAD1/67 in the MDA-MB-231-BR brain metastatic line. The ABAT enzyme converts GABA into succinate, promoting energy metabolism and tumor interaction with the brain microenvironment. GAD1/67 synthesizes GABA from glutamate and its overexpression is related to greater proliferation, migration and tumor invasion. Inhibition of these enzymes may elucidate therapeutic targets of TNBC. Vigabatrin, an irreversible ABAT inhibitor, prevents the conversion of GABA to succinate. Aliglycin, isoniazid and hydrazine inhibit GAD, reducing GABA synthesis and increasing neuronal excitability. Hydrazine, due to its low lipophilicity, has limited ability to cross the blood-brain barrier and may act peripherally, delaying metastasis. In addition to the GABAergic pathway, purinergic signaling also influences tumor progression, modulating cell proliferation and migration. Data from our group revealed that antagonism of P2X7 and P2Y2 receptors disrupted GABAergic differentiation from TNBC tumor stem cells, suggesting that purinergic and GABAergic signaling are involved in regulating the metastatic process of migration, differentiation and brain colonization in tumor cells. Therefore, we propose to investigate the effects of P2X and P2Y purinergic receptor agonists and antagonists, in addition to the inhibition of GAD1/67 and ABAT on the proliferation, migration and viability of TBNC cells, to understand the mechanisms of TNBC brain metastasis and explore possible therapeutic targets.