GABA(B1e) promotes the malignancy of human cancer cells by targeting the tyrosine phosphatase PTPN12

Neurotransmitter receptors are involved in cancer progression. Among them, the heterodimeric GABA(B) receptor, activated by the main inhibitory neurotransmitter GABA, is composed of the transmembrane GABA(B1) and GABA(B2) subunits. The oncogenic role of the isoform GABA(B1e) (GB(1e)) containing only the extracellular domain of GABA(B1) remains unclear. We revealed that GB(1e) is largely expressed in human breast cancer (BrCa) cell lines as well as in BrCa tissues where it is upregulated. Moreover, GB(1e) promoted the malignancy of BrCa cells both in vitro and in vivo. We propose that GB(1e) favors EGFR signaling by interacting with PTPN12 to disrupt the interaction between EGFR and PTPN12, and phosphorylation of Y230 and Y404 on GB(1e) is required in this process. Our data highlight that the GABBR1 gene through the expression of the GB(1e) isoform might play an important oncogenic role in BrCa and that GB(1e) is of interest for the treatment of some cancers.