PROJECT SUMMARY Over half of breast cancer deaths occur later than 5 years after initial diagnosis and treatment. In these cases of recurrent breast cancer, patients have no detectable tumor burden following treatment, suggesting that a small population of malignant cells is able to survive therapy and remain dormant for years. Despite the high risk of recurrence in breast cancer, the cellular properties of cancer cells that evade therapy and survive in a dormant state are largely uncharacterized. In particular, the metabolic requirements of dormant and recurrent tumor cells remain unknown. To address this, our lab uses a transgenic mouse model that recapitulates many of the features of dormancy and recurrence in breast cancer. In this model, doxycycline administration to bitransgenic MMTV-rtTA;TetO-Her2 (MTB/TAN) mice leads to Her2 expression and the formation of invasive mammary adenocarcinomas. Removal of doxycycline causes Her2 down-regulation and induces tumor regression. However, a small population of cells persists in a dormant state before eventually re-initiating proliferation to form a recurrent tumor. I have used this model to generate in vitro cultures, and I can study the process of tumor dormancy and recurrence both in vivo and in vitro. In preliminary studies, I have shown that Her2 inhibition leads to profound metabolic changes accompanied by the generation of reactive oxygen species (ROS). The master transcription factor that mediates the cellular antioxidant response, NRF2, becomes activated following Her2 inhibition, and recurrent tumors exhibit persistent NRF2 activation. NRF2 has well documented oncogenic roles in lung and liver cancers, but a functional role for its activation following anti-Her2 therapy remains uncharacterized. However, antioxidants can rescue cell death following Her2 inhibition, suggesting that cells which deploy a robust NRF2-regulated antioxidant response may preferentially survive following Her2 inhibition. Based upon these preliminary data, I propose to characterize the functional effects and mechanistic basis of oxidative stress and NRF2 activation during tumor regression, dormancy and recurrence.

PROJECT NARRATIVE Over half of breast cancer patient deaths occur later than 5 years after diagnosis and treatment, highlighting the clinical problem of breast cancer recurrence. Utilizing a mouse model that mimics key aspects of breast cancer dormancy and recurrence, I seek to study the regulation and functional significance of cancer cell metabolism during this process. Very little is known about the metabolic consequences of inhibiting oncogenic signaling, and this information can uncover therapeutic targets for dormant and recurrent tumors to reduce breast cancer related deaths.