Characterization of a Novel Recurrent Noncoding Genomic Alteration in Breast Cancer
Abstract
This application is in response to the overarching challenge: Identify what drives breast cancer growth; determine how to stop it. Genomic alterations drive breast cancer growth. The human genome is made up of all the deoxyribonucleic acid (DNA) contained in our cells. Our DNA is made up of six billion individual DNA "letters," which are packaged into chromosomes. Just like the letters in a book make up words to tell a story, so do the letters in our genomes, which make up genes that ultimately produce proteins. In breast cancer cells, small changes in these genetic letters can significantly alter what a genomic word or sentence means. For example, a change in a single letter can lead to the production of a protein that doesn t allow the cell to work as it should. Breast cancer is a genetic disease involving multi-step changes in the genome. By studying the breast cancer genome, scientists can discover what letter changes are causing a cell to become cancerous. One of the best known examples is the discovery of the HER2 amplification (i.e., multiple identical copies of a DNA sequence) in patients with breast cancer, which has led to the successful development of the anti-cancer drug trastuzumab (Herceptin), a monoclonal antibody that interferes with the HER2 protein. Studies to identify genetic drivers in breast cancer have been focused mainly on protein-coding genes. The sequence of a gene is like a language that instructs the cell to manufacture a particular protein or a functional ribonucleic acid (RNA). There are two major steps in the translation of a gene to a protein: the DNA on which the gene resides is transcribed from DNA to RNA, and the RNA is then translated into a protein. Protein-coding RNA (also called messenger RNA; mRNA) therefore serves as an "intermediate language" in the translation of a gene s message into a protein s amino acid sequence. In contrast, non-coding RNA refers to a functional RNA molecule that is not translated into a protein. Before the discovery of non-coding RNA genes in cancer, the search for novel genes that drive the development of cancer was focused mainly on protein-coding genes that resided in recurrent alterations in cancer genomes. However, in breast cancer genomes, it was determined that many of these recurrent alterations were located in protein-coding gene "desert" regions or they contained no cancer-causing protein-coding genes. The lack of protein-coding genes in cancer-associated genetic alterations is further supported by the fact that only 2% of the human genome encodes proteins, while over 30% of the genome is altered in cancer. These findings, in combination with the recent revelation that about 70% of the human genome is transcribed into RNA, strongly suggest that non-coding RNAs may play significant roles in breast tumor development. Long non-coding RNAs are a new class of cancer-driving genes with translational potential in breast cancer. The human genome contains ~25,000 protein-coding genes, representing less than 2% of the total genome, whereas up to 70% of the human genome is transcribed into RNA, yielding many thousands of non-coding RNAs. The recent discovery of long non-coding RNA (lncRNA) genes may dramatically alter our understanding of breast cancer. LncRNAs are operationally defined as RNA transcripts larger than 200nt that do not appear to have protein coding potential. Several lncRNAs, such as HOTAIR and Xist, have been demonstrated to serve as oncogenes or tumor suppressors in breast cancer. Thus, lncRNAs represents the cutting edge of cancer research. Investigation of the functions of lncRNAs in cancer will lead to a greater understanding of the molecular mechanisms of this disease and should lead to novel clinical applications in oncology. The Principal Investigator s (PI s) laboratory has long-standing experience in the investigation of non-coding RNAs in breast cancer. Our studies have demonstrated that lncRNAs are alte
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510041
Entities
People
- Lin Zhang
Organizations
- United States Army
- University of Pennsylvania