Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases and is characterised by the absence of estrogen, progesterone and HER2 receptors. Unlike other breast cancer subtypes, there are currently few targeted therapies for TNBC and chemotherapy remains the current standard of care. Unfortunately, the prognosis for patients with residual disease following chemotherapy treatment is poor. The molecular basis of chemotherapy resistance in TNBC is poorly understood.
Reprogramming of cell metabolism is now firmly established as a hallmark of cancer that promotes tumourigenesis by enabling uncontrolled proliferation and cell survival. Cancer cell metabolism is influenced by a variety of cell-intrinsic and cell-extrinsic factors. Research in the field has focussed on understanding how cell-intrinsic factors, in particular oncogenic mutations, impact cancer cell metabolism. However, there has been a recent paradigm shift in the field toward the understanding that cancer cell metabolism is heavily influenced by cell-extrinsic factors including nutrient availability and therapy exposure. We have previously demonstrated that adaptive reprogramming of cell metabolism occurs in response to chemotherapy exposure and directly promotes chemotherapy resistance in TNBC. This information permitted the identification of a novel combination therapy regimen to improve the efficacy of chemotherapy for treating TNBC.
Our current studies seek to understand how nutrient availability impacts mechanisms of chemotherapy resistance in TNBC. Taking advantage of a cell culture media that more accurately recapitulates nutrient availability in humans, we have demonstrated that changes in nutrient availability alter the sensitivity of TNBC cells to chemotherapy. In addition, using our physiologically relevant media we have profiled the transcriptome of five TNBC cancer cell lines pre- and post-chemotherapy exposure. We are currently investigating the contribution of chemotherapy-responsive genes to the regulation of the cellular response to chemotherapy. By understanding the impact of nutrient availability on chemotherapy resistance mechanisms we ultimately hope to identify combination chemotherapy strategies to circumvent resistance in TNBC patients.