Enhancing Anaphase Promoting Complex Activity to Counter Multiple Drug Resistant Breast Cancer

Breast cancer is one of the major killers of women today. Multiple drug resistance (MDR) is the primary cause of high mortality rates and recurrence rates observed in patients diagnosed with this disease. MDR is defined as the ability of cancer cells to survive despite being exposed to a wide range of anti-cancer drugs. There are many underlying causes for the development of MDR and they include defects in DNA repair pathways, dysregulated mitosis, tumor heterogeneity and genomic instability. These characteristics are associated with cell cycle impairments which is why we propose studies aimed at understanding the molecular mechanisms of MDR in breast cancer by investigating the Anaphase Promoting Complex (APC). The APC is an E3 ubiquitin ligase that targets many substrates for proteasomal degradation through polyubiquitination during the M and G1 phases of the cell cycle. Studies in the yeast species Saccharomyces cerevisiae have provided evidence that the activated APC interacts with several stress response pathways, antagonizing genomic instability, leading to anticancer effects. Furthermore, many APC substrates are routinely observed to be elevated in cancer cells suggesting that APC function is impaired. Increasing activity of the APC may push malignant cells through premature mitosis while harboring high levels of chromosome instability, resulting in mitotic catastrophe and death of MDR cells. When combined with DNA damaging chemotherapy, premature progression of MDR cells through mitosis could be even more debilitating. Therefore, we hypothesize that increasing the activity of the APC through novel binding and activating peptides will slow cancer cell migration, tumor growth and will behave synergistically with chemotherapy agents. We found that the APC binding peptides identified in yeast decreased cancer cell viability, migration and tumor growth after being transfected into an MDR cancer cell line. Additionally, protein markers indicative of genomic instability and apoptosis were increased in cells expressing the peptides. When combined with the anti-cancer agents, doxorubicin and M2I-1, we also found that peptide expressing tumors were of a smaller volume than our controls. The results of this study suggest that enhancing APC activity may restore chemosensitivity in MDR cells yet the precise interaction between the APC and the peptides requires further investigation