Novel Functions of EZH2 in Triple-Negative Breast Cancer: Translation into New Biomarker and Treatment Strategies
Abstract
Background: Triple-negative breast cancer (TNBC) is a label used for invasive breast cancers that don t express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor (Her2) and thus do not respond to drugs that target these factors. Current treatments for TNBC are sorely lacking, leaving it as the type of breast cancer with the worst survival. However, not all patients with TNBC are alike. We, and others, are working to discover tumor markers that are present in subsets of women with TNBC, so as to develop drugs that will be effective at killing their cancers. Our laboratory has discovered that EZH2 protein is approximately 55% of invasive breast carcinomas, and its expression is associated with the TNBC subtype. We also reported that elevated EZH2 protein predicts cancers that are more likely to metastasize. EZH2 is also elevated in some non-breast solid tumors. Studies have shown that EZH2 is primarily a nuclear protein, where it functions as a transcriptional repressor. However, in TNBC we discovered that EZH2 has other, previously undescribed functions. While studying breast cancer from Ghanaian women, we discovered that 16% of TNBC expresses EZH2 in the cytoplasm (instead of in the nucleus), and interacts with two other proteins that are important in breast cancer progression and may explain why high EZH2 breast cancer is especially aggressive. Overarching Challenges Addressed: (1) Distinguish aggressive from less aggressive TNBC. (2) Identify what drives breast cancer growth and metastasis. We will also look at differences breast cancer between white, African American (AA), and African women. Objective/Hypothesis: Our novel hypothesis is that EZH2 protein is high in the cytoplasm of the cancer cells in a subset of TNBC tumors and through a new mechanism and leads to rapid metastasis. Specific Aims: (1) To investigate whether the increased cytoplasmic expression EZH2, along with other tumor markers we have investigated, identifies aggressive breast cancer TNBC tissue samples of African, AA, and white women. (2) To carry out the biochemical and biophysical characterization of the EZH2 interaction with other proteins. (3) To understand the relevance of EZH2 and other markers in TNBC invasion and metastasis in studies of cell lines and mice. Impact: While the role of EZH2 in breast and other cancers has been shown, the mechanisms are not fully understood. We propose a novel mechanism of action for EZH2 specifically in TNBC, which could lead to new ways to treat TNBC that express EZH2 in the cytoplasm, patients for whom current therapies have limited benefit. We believe that our work will offer a new mechanistic-based approach to block metastasis in this group of tumors. Given that TNBC is more common in AA than white women, this work could reduce racial disparities in treatment of breast cancer. Additionally, since TNBC is especially common in Africa, the work could prove especially important for global health.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510020
Entities
People
- Zaneta Nikolovska-coleska
Organizations
- United States Army
- University of Michigan