The breast cancer susceptibility gene product (γ-synuclein) alters cell behavior through it interaction with phospholipase Cβ

The breast cancer susceptibility gene protein, also known as γ-synuclein, is highly expressed in human breast cancer in a stage-specific manner, with highest expression in late stage cancer. In model systems, γ-synuclein binds phospholipase Cβ2 which is regulated by Gαq to generate intracellular Ca2 + signals. PLCβ2, which is also absent in normal tissue but highly expressed in breast cancer, is additionally regulated by Rac to promote migration pathways. We have found that γ-synuclein binds to the same region of PLCβ2 as Gαq. Using cells that mimic stage 4 breast cancer (MDA MB 231), we show that down-regulation of γ-synuclein reduces the protein level of PLCβ but increases the transcript level over 40 fold. γ-Synuclein down-regulation also promotes the interaction between Gαq and PLCβ resulting in a stronger Ca2 + response to Gαq agonists. The ability of γ-synuclein to interfere with Gαq-PLCβ interactions allows more PLCβ to colocalize with Rac impacting Rac-mediated pathways that may give rise to cancerous phenotypes.