A LONG, STRESS-RESPONSIVE, NONCODING TRANSCRIPT (NIT 5) AND ITS ROLE IN THE DEVELOPMENT OF BREAST CANCER

Project: Research project

Project Details

Description

Background: Most of the focus in breast cancer genetics has been the study of specific genes whose alteration either predisposes or is involved in breast cancer development. However, less than 2% of the human genome actually is involved in coding for protein. It has recently become clear that much of the non-coding portion of the genome is still transcriptionally active and that non-coding transcripts vastly exceed coding transcripts. The non-coding transcripts have been found to play important regulatory roles within cells including breast cancer cells. We have now identified a group of long stress-responsive non-coding transcripts that appear to be involved in promoting cellular proliferation in breast cancer.Objective: We propose to characterize one of the newly identified stress responsive long non-coding transcript as this transcript is derived from a chromosomal region frequently amplified in breast cancers and it is overexpressed in most breast cancers cell lines and primary tumors tested to date. Our hypothesis is that this non-coding transcript is representative of a new group of transcripts that promote proliferation and as such are important targets during breast tumorigenesis. We will characterize this transcript to determine the role that it plays in the development of breast cancer and determine the genes and pathways that it is involved in regulating. This and other long stress-responsive non-coding transcripts might be novel therapeutic targets for the treatment of breast cancer.Specific Aims: There are three specific aims to this proposal. The first specific aim is to fully characterize this transcript including determining where it begins and ends, its localization within both normal breast epithelium and in breast cancers, and to identify where and when it is overexpressed. The second specific aim is to knock down the expression of the overexpressed transcript in breast cancer cell lines and also to overexpress it in normal breast epithelial cell lines. We will then observe the resulting phenotypic effect of modulating the expression of this transcript. The third specific aim is to characterize the effect of this modulation on the entire transcriptome using Next Generation DNA sequencing on the SOLID/ABI platform.Innovation: This study is examining a newly identified stress-responsive non-coding transcript as a representative of a new group of regulatory transcripts that play an important role in the development of breast cancer. Little work has been done characterizing the role that long non-coding transcripts play in breast cancer development. Several of the considerably shorter microRNAs have been found to play important regulatory roles and to be important targets in breast tumorigenesis. There have been recent discoveries suggesting that the role of non-coding transcript is to regulate coding gene expression. We believe that our stress-responsive long non-coding transcript promotes cellular proliferation and is just one of possibly many long non-coding transcripts that could be involved in breast cancer development. After modulating its expression and observing the resulting phenotypic changes that it has on normal breast epithelial cells, we will use the power of Next Generation DNA sequencing to examine the effect it has on the entire transcriptome of the breast cells, not just on the coding portion of the genome.Impact: The identification and characterization of regulatory small microRNAs have revealed that several miRNAs are important targets of alteration in the development of breast cancer. We believe that the longer stress-responsive non-coding transcripts are also important cellular regulators that play an important role in breast tumorigenesis. They may also be important therapeutic targets. Hence, we believe that these studies will reveal new transcripts that play important roles in breast cancer development.

StatusFinished
Effective start/end date8/1/108/31/13

Funding

  • Congressionally Directed Medical Research Programs: $566,625.00

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