Long nuclear retained non-coding RNAs (IncRNAs) represent a large and relatively unmined class of RNAs that are likely to play critical roles in gene regulation and disease etiology. A major challenge is to understand the molecular functions of specific IncRNAs both at the cellular level and within the context of an organism. The long-term goal of this project is to identify and characterize IncRNAs that play a critical role in mammary gland development and the initiation and progression of breast cancer. Here, a series of Aims are presented to dissect out the role of Malati, an abundant IncRNA localized to nuclear speckles and focally amplified in a significant number of metastatic breast cancers. Studies are proposed to develop innovative loss-of-function and gain-of-function mouse models combined with cell biological approaches to assess the function of Malati in normal development and in breast cancer initiation and metastasis. The impact of alterations in the level of Malati on tissue organization will be examined, and its effect on alternative splicing in a tissue-specific manner will be pursued by next-generation RNA-sequencing analyses. Complementary cell biological studies will delve into the role that Malati plays in nuclear organization and its impact on the dynamics of pre-mRNA splicing factors enriched in nuclear speckles. The Malati RNP will be purified using an RNA-tagging strategy and its proteome will be characterized in order to identify proteins responsible for its nuclear retention and to provide additional insight into its function. In the final Aim a series of newly identified IncRNAs, that are misregulated in breast cancer, will be prioritized and several will be selected for functional analyses, to identify genes and pathways that they target, and to elucidate the mechanisms by which they contribute to breast cancer tumorigenesis. Together, the proposed studies will provide important insights into the role of several IncRNAs in normal development and cancer and will lead to new opportunities for the identification and characterization of a new and exciting class of potential therapeutic targets.

Public Health Relevance

This study will examine the role of several long nuclear retained non-coding RNAs in mouse development and in the initiation and progression of breast cancer. LncRNAs represent a relatively new and unexplored class of potential diagnostic and therapeutic targets with roles in regulating aspects of gene expression. The insights gained from the proposed studies will add significantly to our understanding of breast cancer and potential treatment options.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA013106-43
Application #
8744359
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
43
Fiscal Year
2014
Total Cost
$395,272
Indirect Cost
$188,666
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
Li, Meng Amy; Amaral, Paulo P; Cheung, Priscilla et al. (2017) A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation. Elife 6:
Diermeier, Sarah D; Spector, David L (2017) Antisense Oligonucleotide-mediated Knockdown in Mammary Tumor Organoids. Bio Protoc 7:
Pelossof, Raphael; Fairchild, Lauren; Huang, Chun-Hao et al. (2017) Prediction of potent shRNAs with a sequential classification algorithm. Nat Biotechnol 35:350-353
Roe, Jae-Seok; Hwang, Chang-Il; Somerville, Tim D D et al. (2017) Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis. Cell 170:875-888.e20
Zhang, Bin; Mao, Yuntao S; Diermeier, Sarah D et al. (2017) Identification and Characterization of a Class of MALAT1-like Genomic Loci. Cell Rep 19:1723-1738
Mu, Ping; Zhang, Zeda; Benelli, Matteo et al. (2017) SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355:84-88
Anczuków, Olga; Krainer, Adrian R (2016) Splicing-factor alterations in cancers. RNA 22:1285-301
Baker, Leena; BeGora, Michael; Au Yeung, Faith et al. (2016) Scribble is required for pregnancy-induced alveologenesis in the adult mammary gland. J Cell Sci 129:2307-15
Tasdemir, Nilgun; Banito, Ana; Roe, Jae-Seok et al. (2016) BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov 6:612-29
Hossain, Manzar; Stillman, Bruce (2016) Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription. Elife 5:

Showing the most recent 10 out of 592 publications