Therapeutically targeting metabolic vulnerabilities in breast cancer
Cancer cells commonly exhibit alterations in carbon metabolism, namely of glucose, fatty acids, and amino acids. While the benefits of such alterations to cancer cells remain under study, it is generally thought that cancer cells do not fully metabolize glucose to provide building blocks for other anabolic pathways (“the Warburg effect” of aerobic glycolysis). We found that estrogen receptor alpha (ER)-positive breast cancer cells increase mitochondrial respiration when confronted with the stress of anti-estrogens that block ER transcriptional activity. Mitochondrial alterations have been observed in other cancer types under treatment with anti-cancer drugs, suggesting that this may be a widespread mechanism that promotes drug resistance. Our ongoing studies are testing the therapeutic tractability of inhibiting mitochondrial oxidative phosphorylation to kill ER+ breast cancer cells and prevent disease recurrence.
Mitochondria are a major site of fatty acid oxidation, the process through which fatty acids are broken down to yield substrates that feed the TCA cycle and, ultimately, provide metabolites that feed mitochondrial respiration. A high-fat diet promotes anti-estrogen resistance in ER+ breast cancer in mice. We are currently testing the therapeutic potential of inhibiting fatty acid uptake and synthesis by ER+ breast cancer cells.
Following recurrence of estrogen receptor alpha (ER)-positive breast cancer, advanced/metastatic disease is managed with further anti-estrogen therapies, targeted therapies, and DNA-damaging chemotherapies. Nearly all metastatic breast cancers eventually become completely refractory to these therapies. Prior to the approval of tamoxifen, estrogens were frequently used for the treatment of breast cancer. This may seem counterintuitive since we now rely on anti-estrogens for disease management, but response rates to estrogens are similar to those of anti-estrogens in the setting of advanced disease. Approximately 1/3 of anti-estrogen-resistant breast cancers respond to estrogen therapy, translating into ~100,000 new patients each year who could benefit. Similarly, some cancers respond to withdrawal of anti-estrogen therapy, which may be caused by ER transcriptional reactivation. Breast tumor responses to estrogen therapies and anti-estrogen withdrawal have been observed for >70 years, but the lack of A) understanding of the therapeutic mechanism(s), and B) criteria to identify patients likely to benefit have hindered clinical use.
