TAZ-driven Regulation of Tumor Microenvironment in Triple-Negative Breast Cancer

ABSTRACT Breast cancer (BC) is a complex and heterogeneous neoplastic disease with a high incidence and mortality. BC can be divided into clinical, histopathologic, and molecular subtypes. Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases and is characterized by tumors that do not express

the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC is thought to be the most aggressive subtype and is associated with a poor prognosis, as well as a high risk of distant recurrence and death within the first 3–5-years of follow-up. The absence of these receptors

renders TNBC resistant to treatments targeting those pathways. Thus, TNBC still remains a neoplastic disease with unmet clinical challenges. Our laboratory has previously demonstrated an integral tumor-intrinsic role of TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1), which is a key component of

the Hippo signaling pathway found in TNBC progression/metastasis. New preliminary data in our laboratory indicate that tumor TAZ expression inhibits tumor progression in mouse models of TNBC cells in immune system intact mice, thus indicating that TAZ expression also plays an underappreciated extrinsic role in TNBC biology.

We further revealed that TAZ regulates the recruitment and/or function of immune suppressive cells, such as myeloid-derived suppressor cells (MDSCs), macrophages and regulatory T cells (Tregs). The overall objective of this proposal is to understand the underlying molecular mechanisms by which TAZ expression in tumor cells

regulates immune suppressive cells in TNBC. Our central hypothesis is that tumor TAZ expression regulates the TME landscape via cross-talk between cancer cells with non-cancer immune suppressive cells. Our long-term goal is to decipher TAZ regulated crosstalk between breast tumor cells and the immune components within the

tumor microenvironment (TME) to uncover new prognostic or therapeutic targets for TNBC. To achieve these goals, we propose the following two aims: 1) To determine the impact of tumor-intrinsic TAZ expression on the immune-TME; and 2) To understand the molecular mechanisms of TAZ expression driven immune suppressive

cells recruitment in TME. A major impact of this study is to identify previously undescribed TAZ-mediated mechanisms that will unveil new biomarkers or inform novel therapeutic interventions for advanced TNBC.