Tumor progression ? including resistance to therapy, metastasis, and recurrence ? is responsible for the majority of cancer deaths. Understanding how cancer cells survive treatment, spread to distant sites, persist as dormant residual cells, and eventually recur is essential to improving the treatment of this disease. Our long-term goal is to identify the pathways that regulate these processes in order to prevent or treat tumor recurrence. To achieve this we are using conditional genetically engineered mouse (GEM) models of breast cancer that allow for the mechanistic dissection of the processes of dormancy and recurrence. Using these models, we have identified a functional role for the tumor suppressor par-4 in regulating survival and recurrence of breast cancer cells after therapy. Par-4 is down-regulated in recurrent tumors from three GEM models, and this down-regulation is both necessary and sufficient for tumor recurrence. Similarly, in women with breast cancer, low par-4 expression is associated with a poor response to neoadjuvant therapy and an increased risk of recurrence. However, nothing is known about the upstream pathways that regulate par-4 during dormancy and recurrence. In addition, it is not known what downstream pathways par-4 regulates to inhibit dormant cell survival and recurrence, or how par-4 affects metastasis. This proposal will address these questions.
In Aim 1, we will elucidate the pathways that regulate par-4 following oncogene inhibition and in recurrent tumor cells, and determine how these contribute to dormant cell survival and recurrence.
In Aim 2, we will identify the molecular pathways regulated by par-4 expression, and determine how these contribute to dormant cell survival and recurrence.
In Aim 3, we will dissect the temporal requirements for par-4 down-regulation during dormancy, recurrence, and metastasis. Our work will provide insight into the regulation and function of par-4 during tumor recurrence and may identify opportunities to develop therapies that target dormant cells and prevent tumor recurrence.

Public Health Relevance

Breast cancer is the most common cancer in women worldwide and among the leading causes of death in women, and the vast majority of breast cancer deaths result from tumor recurrence at distant sites following treatment. Understanding how tumor cells survive treatment, persist as dormant cells, and eventually reinitiate malignant growth is essential to developing therapies to kill dormant cells and prevent breast cancer recurrence. We have shown that the tumor suppressor protein par-4 is a critical negative regulator of breast cancer recurrence. In this proposal we will build on this finding to elucidate the regulation and function of par-4 in dormant cell survival and recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Woodhouse, Elizabeth
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Duke University
Schools of Medicine
United States
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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
Mabe, Nathaniel W; Fox, Douglas B; Lupo, Ryan et al. (2018) Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer. J Clin Invest 128:4413-4428