Over half of breast cancer related deaths are due to recurrence of breast cancer 5 or more years after initial diagnosis and treatment. This latency of recurrence suggests that a population of residual tumor cells can survive treatment and lay dormant for many years. The mechanisms regulating dormant cell survival remain unknown. Accumulating evidence suggests that the tumor microenvironment may be a key regulator of tumor dormancy, but the lack of appropriate in vivo models makes this difficult to study. To address this, we are using a mouse model of breast cancer that recapitulates dormant disease and eventual recurrence. Doxycycline administration leads to Her2 overexpression and the development of mammary tumors. Withdrawal of doxycycline induces Her2 down-regulation and causes tumors to regress. After a period of latency, tumors recur under Her2 independent mechanisms. In preliminary studies, I have used antibody arrays to gain insight into how the expression of critical cytokines changes during dormancy and recurrence. These results suggest that CCL5, a chemoattractant cytokine, is significantly higher in dormant and recurrent tumors versus primary tumors, and that macrophages are recruited to dormant tumors after Her2 down-regulation. In this proposal I will explore the functional role of the microenvironment, including CCL5 and macrophages, in tumor dormancy and recurrence.
In Aim 1, I will define the role of CCL5 in tumor dormancy, recurrence, and macrophage recruitment.
In Aim 2, I will identify the function of macrophages in the dormant tumor microenvironment.
In Aim 3, I will identify cytokines that regulate the survival and/or proliferation of dormant tumors.
Over half of breast cancer related deaths are due to breast cancer recurrence 5 or more years after initial diagnosis and treatment. Utilizing a mouse model that mimics dormancy and recurrence as it occurs in women, we propose to explore how the tumor microenvironment regulates breast cancer recurrence. This may allow for the identification of microenvironmental factors that can be therapeutically targeted to improve breast cancer survival.
|Damrauer, Jeffrey S; Phelps, Stephanie N; Amuchastegui, Katie et al. (2018) Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K-Akt Inhibition. Mol Cancer Res 16:599-609|