Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation.

Young women with breast cancer are particularly vulnerable to FCR. The present study provides preliminary evidence that FCR is associated with higher health costs and lower surveillance rates which may compromise health outcomes. Routine screening for FCR in follow-up care is recommended.

The aim of this systematic review was to identify the prevalence and severity of upper limb problems following surgery and radiation for early breast cancer. Additionally, the independent prognostic contribution of radiation, type of breast surgery, type of axillary surgery, age and body mass index (BMI) was evaluated. Searches of electronic databases were conducted to identify articles that reported upper limb and quality of life outcomes after breast cancer surgery and external radiation. Eligible studies for prognosis were longitudinal in design, with > or =95% of patients treated by surgery and radiation that excluded the axilla. Cross-sectional studies were also included for identification of prognostic factors. Where possible, the contribution of independent prognostic factors was analyzed. The review identified 32 relevant studies. Shoulder restriction was reported in between <1% and 67% of participants, lymphedema was reported in between 0 and 34% of participants, shoulder/arm pain was reported in between 9 and 68% of participants and arm weakness was reported in between 9 and 28% of participants. Quality of life was high across studies. Irradiated patients had slightly increased odds of lymphedema (OR = 1.46, 95% CI 1.16-1.84) and shoulder restriction (OR = 1.67, 95% CI 0.98-2.86) compared with non-irradiated patients. For patients undergoing surgery and radiation for breast cancer, the prognosis is good in terms of the upper limb and quality of life. Radiation that excludes the axilla does not appear to be a strong prognostic indicator of adverse upper limb outcomes.

While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour-infiltrating lymphocytes (TILs) and PDL1 expression in this cohort.