Role of RNA Methylation in microRNA Processing and Breast Cancer Tumorigenesis and Metastasis
Abstract
To become cancerous, cells undergo two major alterations: they either mutate the genetic information contained within our DNA or they change the way that genetic information is expressed from DNA to RNA to proteins. To control the expression of our genetic information, cells decorate DNA, RNA, or proteins with small chemical marks, including methylation. Drugs that target "writers" or "erasers" of methylations on DNA or proteins are either already being used in the clinic or are the subject of promising clinical trials to treat cancer. In contrast, the study of RNA methylation has been limited mainly due to technical challenges for its detection. Here, we aim to overcome these challenges and validate RNA methylation as a new avenue for anti-cancer drug discovery. In particular, we will focus on a new "writer" of methylation called NSUN5. Our preliminary studies have shown that NSUN5 is expressed in cancer but not in normal breast tissue of patients with aggressive breast cancer. Moreover, overexpression of NSUN5 is associated with a shorter time of disease-free survival in breast cancer patients. This is especially significant in younger breast cancer patients below 40 years of age. Taken together, these are strong indications for the involvement of NSUN5 in cancer. Our hope is that by inhibiting NSUN5 with drugs, we will be able to provide better treatment for younger patients who usually suffer poorer outcomes with breast cancer than older patients. We have two main goals in the proposal. Our first goal is to perform all the experiments that are a prerequisite for a drug discovery program. This involves the full characterization of the "writer" to determine how, where, when, and why does NSUN5 "write" this mark on RNA, as well as whether inhibiting this "writer" with molecular biology methods abolishes the cancerous identity of breast cancer cells. Our second goal is to establish new tools to detect these marks on RNA from fixed tumor samples, information that could eventually help us to determine which patients could benefit from inhibiting NSUN5 activity. Thus, our proposed work addresses two or more of the Breast Cancer Research Program overarching challenges including: "identify what drives breast cancer growth; determine how to stop it" and "identify why some breast cancers become life-threatening metastasis." Our studies will impact breast cancer research in more than one way. In the short to medium term, given that NSUN5 is overexpressed in invasive breast cancers and that its overexpression is significantly correlated with shorter disease-free survival in younger breast cancer patients, our studies have the potential to validate a target for anti-cancer drug discovery targeted at this age group in which breast cancer has inferior clinical outcomes. In the longer term, the establishment of innovative methods and tools for the study of RNA methylation in cancer is bound to open new, previously unexplored, avenues for the detection, categorization, and treatment of breast and other cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610352
Entities
People
- Blerta Xhemalce
Organizations
- United States Army
- University of Texas at Austin