Blocking Breast Cancer Metastasis by Targeting RNA-Binding Protein HuR
Abstract
In the past decades, extensive efforts have been made towards improving diagnosis and breast cancer treatments. However, breast cancer is still the most commonly diagnosed cancer among women (accounting for 29% of newly diagnosed cancers) and is the second most common cause of female death from cancer. The National Cancer Institute estimates that in 2014, approximately 232,670 women in the United States will be diagnosed with breast cancer and 40,000 will die from this disease. Currently, the majority of chemotherapies used to treat breast cancer induce cell death without any consideration for inhibiting specific tumor-promoting proteins, or oncoproteins, that drive the tumor cell proliferation in the first place. Metastatic breast cancer is very resistant to chemotherapy or radiation therapy due to the overexpression of the various tumor-driving oncoproteins. Current and future efforts toward designing and developing new therapies specifically target those oncoproteins that confer breast cancer cell growth and resistance. This strategy of developing molecularly targeted therapies will improve survival and quality of life of breast cancer patients by increasing specificity and reducing toxicity. The oncoprotein Hu antigen R (HuR) is overexpressed in many types of cancers, including breast cancer. The cellular location of HuR protein in the cytoplasm versus nucleus correlates with high-grade malignancy and poor distant disease-free survival, a prognostic factor of poor clinical outcome in breast cancer. Our preliminary data also show that reducing HuR levels in breast cancer cells delays tumor initiation and growth. HuR is an RNA binding protein that promotes mRNA stability and translation of its target oncogenes, such as Musashi 1/2, Bcl-2, and XIAP. This results in increased breast cancer cell growth, progression, and metastasis. Moreover, chemotherapy and radiation therapy increase cytoplasmic HuR and subsequently its target genes, thus rendering breast cancer cells resistant to both therapies. Taken together, these findings support HuR as a promising target for breast cancer therapy. We hypothesize that small molecule compounds that disrupt HuR-mRNA interaction will block HuR function, leading to inhibition of cell growth and tumor progression in breast cancer cells with high levels of HuR. The goal of this proposal is to obtain a series of small molecule compounds as chemical probes that potently bind to HuR and inhibit its functions. Ultimately, we will select the 1-2 most drug-like lead compounds for further development as a whole new class of molecular cancer therapy that inhibit breast cancer with HuR overexpression. Towards this goal, we currently have several potent hits, and in this proposal we will computationally modify the structure of the compounds in order to increase the ability of these compounds to inhibit HuR and cancer growth. The new modified compounds will be tested on breast cancer cells to see whether they inhibit HuR-mRNA binding and possess anti-tumor activity. This proposal aims to address the following overarching challenges: (1) Eliminate the mortality associated with metastatic breast cancer; and (2) identify why some breast cancers become life-threatening metastasis. Advanced, metastatic breast cancer is associated with increased resistance to conventional chemotherapy, together with high oncogenic signaling due at least in part to high levels of HuR in breast cancer patients. The proposed study will provide a proof-of-concept for targeting the RNA-binding protein HuR as a novel therapeutic modality for metastatic breast cancer with high levels of HuR oncogenic signaling. In addition, we will establish our novel and potent HuR inhibitor as a new molecular therapy for blocking breast cancer metastasis and improving the survival of breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610729
Entities
People
- Liang Xu
Organizations
- United States Army
- University of Kansas