GABA–GABA A Receptor Signaling Orchestrates Invasion and Metastasis in Triple Negative Breast Cancer

ABSTRACT Cancer is a leading cause of death globally, with the majority of cancer-related deaths resulting from cancer metastasis -the process by which cancer cells disseminate to distant sites. To metastasize, cancer cells acquire traits in support of diverse cellular processes that enable dissemination, survival, and colonization. Tumor cell dissemination requires invasion at local and distant sites and this process can be influenced by intrinsic and extrinsic factors. Here, we investigate the role of the neurotransmitter gamma-aminobutyric acid (GABA) in triple-negative breast cancer (TNBC) invasion and metastasis. TNBC cells increased invasion in response to GABA and this was found to be mediated through the GABA A receptor family. TNBC cell lines were found to be responsive to exogenous GABA and also produced endogenous GABA. Pharmacological inhibition of GABA A receptors reduced TNBC invasion and cancer cell dissemination and resulted in inhibition of GSK3α activity. TNBC cell lines were found to express the GABRE subunit and loss of GABRE impaired GABA-mediated invasion and tumor cell dissemination. These findings support a role for GABA signaling through GABA A receptors in mediating TNBC progression.