Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple negative breast cancer
GOBERDHAN D., MOROTTI M., El-Ansari R., ZOIS C., Craze M., Rakha E., Fan S-J., Valli A., Haider S., Green A., HARRIS A.
Background Glutamine (Gln) is an abundant nutrient used by cancer cells. Triple negative breast cancers (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in TNBC. Methods The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SNAT2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SNAT2 in a cohort of breast cancer was determined by immunohistochemistry. Results SNAT2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SNAT2. SNAT2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of 44 Gln-sensitive cell lines. High expression of SNAT2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p =0.004), particularly in TNBC (p = 0.02). Conclusions These results position SNAT2 as a selective target for inhibiting growth of Gln-dependent TNBC.