Aberrant expressions of the neuronal protein synuclein gamma (SNCG) in malignant mammary epithelial cells are strongly associated with the progression of breast cancer. SNCG is not expressed in normal breast tissues but abundantly expressed in a high percentage of invasive and metastatic breast carcinomas. Several studies have demonstrated that SNCG expression significantly stimulates proliferation, invasion, and metastasis of breast cancer cells. To elucidate the molecular and cellular mechanisms underlying the tumorigenic functions of SNCG, we investigated the effects of SNCG expression on the mitotic checkpoint function of breast cancer cells. By conducting several different lines of investigations, we now demonstrate that SNCG expression in breast cancer cells overrides the mitotic checkpoint control and confers the cellular resistance to anti-microtubule drug-caused apoptosis. We further show that the inhibitory effects of SNCG on mitotic checkpoint can be overthrown by enforced overexpression of the mitotic checkpoint protein BubR1 in SNCG-expressing cells. These new findings combined with our previous observation that SNCG intracellularly associates with BubR1 together suggest that SNCG expression compromises the mitotic checkpoint control by inhibition of the normal function of BubR1, thereby promoting genetic instability. Genetic instability is recognized as an important contributing factor in tumorigenesis. Hence, our studies gain insight into the mechanisms whereby SNCG expression advances breast cancer disease progression and fasters tumor metastasis.