Circulating SOD2 Is a Candidate Response Biomarker for Neoadjuvant Therapy in Breast Cancer

SIMPLE SUMMARY: The development of specific biomarkers to monitor response to the several available cancer drugs is a major challenge for modern clinical oncology. A reasonable solution for this problem could be to use circulating biomarkers linked to the tumor cell death induced by therapeutic treatment, instead of biomarkers linked to the molecular action of each drug. To test our hypothesis, we selected SOD2, an abundant mitochondrial protein extremely stable. During our studies, we proved that drug-induced tumor cell death increases the plasma levels of SOD2 correlating with the response to neoadjuvant therapy in breast cancer patients. We believe that measuring the circulating levels of SOD2 during therapeutic treatment of advanced cancer patients could offer a simple, non-invasive diagnostic tool complementing standard imaging techniques. ABSTRACT: There is a great need for non-invasive tools that inform of an early molecular response to cancer therapeutic treatment. Here, we tested the hypothesis that proteolytically resistant proteins could be candidate circulating tumor biomarkers for cancer therapy. Proteins resistant to proteolysis are drastically under-sampled by current proteomic workflows. These proteins could be reliable sensors for the response to therapy since they are likely to stay longer in circulation. We selected manganese superoxide dismutase (SOD2), a mitochondrial redox enzyme, from a screening of proteolytic resistant proteins in breast cancer (BC). First, we confirmed the robustness of SOD2 and determined that its proteolytic resistance is mediated by its quaternary protein structure. We also proved that the release of SOD2 upon chemotherapy treatment correlates with cell death in BC cells. Then, after confirming that SOD2 is very stable in human serum, we sought to measure its circulating levels in a cohort of BC patients undergoing neoadjuvant therapy. The results showed that circulating levels of SOD2 increased when patients responded to the treatment according to the tumor shrinkage during neoadjuvant chemotherapy. Therefore, the measurement of SOD2 levels in plasma could improve the non-invasive monitoring of the therapeutic treatment in breast cancer patients. The identification of circulating biomarkers linked to the tumor cell death induced by treatment could be useful for monitoring the action of the large number of cancer drugs currently used in clinics. We envision that our approach could help uncover candidate tumor biomarkers to measure a tumor’s response to cancer therapy in real time by sampling the tumor throughout the course of treatment.