A Long, Stress-Responsive, Noncoding Transcript (NiT 5) and Its Role in the Development of Breast Cancer

Project: Research project

Project Details

Description

It is well known that breast cancer arises when there are a sufficient number of mutations in key genes that are involved in cellular regulation. Much of the focus of cancer research has therefore been on the identification of those important genes. In many instances, an understanding of the genes and molecular pathways involved in breast cancer development has led to better ways to stratify different breast cancers and even to specific therapeutics based upon that understanding. A perfect example of this is the utilization of herceptin in cancers that have amplification of her2/neu. The study of important genes involved in breast carcinogenesis has transformed how we treat and manage patients with breast cancer. However, the portion of the human genome that is devoted to making proteins is less than 2% of the entire genome. The remainder of the genome is not "junk" as previously thought. Recent evidence has shown that much of the genome is involved in making RNA transcripts but that most of those transcripts are not traditional genes involved in coding for protein. Instead, the vast majority of transcripts do not end up coding for protein (these are called non-coding transcripts). The non-coding transcripts are a diverse group of transcripts. Some of the very small transcripts include the microRNAs. These very short transcripts have been shown to be very important regulators of the coding transcripts, and a number of these have been found to be very important targets of alteration during the development of breast cancer. There are also considerably larger non-coding transcripts, and these too have been found to be important cellular regulators. An excellent example of this is a transcript encoded on the X chromosome called XIST. The function of XIST is to coat one of the X chromosomes in women as part of the process of X-chromosome inactivation. This results in inactivation of most of the genes on that X chromosome and is essential for the important process of dosage compensation. Other larger regulatory non-coding transcripts have been identified, and these also appear to play important and diverse regulatory roles within cells. We were very interested in identifying additional important large non-coding transcripts, and we decided to focus on the identification of long non-coding transcripts that had increased expression after cellular stress because of the association between stress and cancer development. We identified a group of these stress-responsive non-coding transcripts and have found that these transcripts appear to regulate cellular proliferation. In this proposal, we would like to characterize one of these transcripts that we have called NiT 5. This is a 2,000 base transcript that has increased expression when breast epithelial cells are exposed to cellular stress. In addition, we have shown that this transcript also has increased expression in most breast cancers that we have studied to date. We also have shown that when we knock down the expression of this transcript, breast cancer cell lines grow more slowly. Our hypothesis is that this transcript is one of a group of new transcripts that help to promote cellular proliferation and that its overexpression promotes the growth of breast cancer cells. We propose to characterize this non-coding transcript to better understand how it is involved in promoting cellular proliferation and its role in the development of breast cancer. Our ultimate goal is to determine if reducing the expression of this and other similar non-coding transcripts could have an important therapeutic effect in women with breast cancer. This study could also help to refocus breast cancer research onto a previously neglected area of breast cancer research, especially considering that the number of non-coding transcripts vastly exceeds the number of coding transcripts.

StatusActive
Effective start/end date1/1/09 → …

Funding

  • Congressionally Directed Medical Research Programs: $566,625.00

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