Par-4 Regulation of Actomyosin Contractility as a Tumor Suppressive Mechanism in Breast Cancer

Project Summary/Abstract 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. The long-term goal of my research group 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 downregulated in recurrent tumors from three GEM models, and this downregulation 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. We have characterized the upstream pathways that regulate Par-4 expression and function during dormancy and recurrence, as well as the downstream pathways that Par-4 regulates to inhibit dormant cell survival and recurrence. This proposal will build on this work to further explore the mechanism by which Par-4 acts as a tumor suppressor. The overarching hypothesis of the proposal is that Par-4 promotes cell death in part through inducing actomyosin contractility, and this contributes to its tumor suppressive functions. We will explore this hypothesis in the context of Par-4’s role in residual cell survival and the survival of invasive lobular cancer cells. Our work will reveal new information on how Par-4 functions to regulate dormant residual cell survival and may uncover novel opportunities for therapeutic intervention in eliminating residual cells and preventing recurrence.