Abstract
BackgroundGlutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (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 breast cancer and TNBC.MethodsThe 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 SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry.ResultsSLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02).ConclusionsThese results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.
Highlights
Glutamine (Gln) is an abundant nutrient used by cancer cells
SLC38A2 mRNA is highly expressed in breast cancer cell lines We examined mRNA and protein levels of several transmembrane Gln transporters such as SLC7A5/LAT1, SLC1A4/ASCT1, SLC1A5/ASCT2, SLC38A1/SNAT1 and SLC38A2/SNAT2 in a variety of breast cancer cell lines representing the luminal (ER+, HER2−; MCF-7 and T47D), HER2+ (SKBR3), basal-like (HCC1806; MDA-MB468, 468) and claudin-low (MDA-MB-231, 231) molecular subtypes of breast cancer (Fig. 1a)
Our results showed that the anti-tumour effect of SLC38A2 blockade in breast cancer cell lines, in the HCC1806 triple-receptor negative breast cancer (TNBC) cell line, in low Gln medium is partially mediated by oxidative stress
Summary
Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. RESULTS: SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. CONCLUSIONS: These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines. The significance of amino acid (AA) metabolism and glutamine (Gln, the most abundant AA in blood serum) in tumour progression has been well recognised, leading to intense interest in therapeutic applications.[1] The maintenance of high levels of AA in cancer cells provides a ready source of carbon and nitrogen to support biosynthesis, energetics and cellular homoeostasis. Triple-negative breast cancer (TNBC), an aggressive form of breast cancer, is dependent on exogenous Gln for survival and growth[4,5] and inhibitors of Gln transport and metabolism have been proposed as potential anti-tumour therapies.[6,7]
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