Cancer cell metabolism has recently been added to the original six Hallmarks of Cancer. This reflects a renewed appreciation of the Warburg effect, whereby cancer cells undergo a metabolic shift toward aerobic glycolysis, resulting in decreased energy production from glucose. The cancer cell’s energy and nutrition needs are subsequently replaced by an increased reliance on the metabolism of amino acids such as glutamine, a process driven by the oncogenic transcription factor MYC. Triple-negative breast cancer (TNBC) expresses high MYC levels, resulting in amplified glutamine metabolic pathways and glutamine addiction. The TNBC subset lacks expression of targetable estrogen receptor, progesterone receptor and HER2 receptor, and is an aggressive cancer that accounts for ~10-15% of all breast cancer cases in Australia and has poor 5-year survival rates. TNBC currently relies on surgery, radiotherapy and chemotherapy, and new targeted therapies are therefore needed for TNBC.
The amplification of glutamine metabolic pathways leads to glutamine addiction in cancer cells. This provides attractive new therapeutic targets such as glutaminase, which is currently being targeted in clinical trials for TNBC. Over the past few years, we have shown that TNBC cells also upregulate the glutamine transporter ASCT2. Chemical inhibition or genetic knockdown of ASCT2 blocks glutamine uptake in TNBC, as well as downstream glutamine metabolism. Furthermore, ASCT2 knockdown blocks cell cycle progression, and induces apoptosis selectively in TNBC compared to Luminal A breast cancer cell lines. Using an orthotopic mammary fat pad xenograft model, we have shown that ASCT2 knockdown blocks tumour formation, and can increase survival in mice with existing tumours. These data suggest targeting ASCT2 is a viable therapeutic strategy in TNBC.