Breast Cancer
Breast Cancer Geneticist Awarded 2017 Breakthrough Prize
Posted April 12, 2017
Stephen J. Elledge, Ph.D., Brigham and Women's Hospital
Stephen J. Elledge, Ph.D., Brigham and Women's Hospital
Dr. Stephen Elledge, world-renowned geneticist and breast cancer researcher at Brigham and Women's Hospital and Harvard Medical School, is a 2017 recipient of the prestigious Breakthrough Prize in Life Sciences, funded by the Breakthrough Prize Foundation. The Breakthrough Prize, the largest individual prize in the world for science, is awarded yearly in recognition of groundbreaking research in the life sciences, fundamental physics, and mathematics. On December 4, 2016, Elledge accepted the $3 million prize for his seminal contributions to the fundamental understanding of cellular biology, including mechanisms by which cells sense and repair DNA damage and insights into the development and treatment of cancer. Over the past 22 years, Elledge has received nine grants from the Department of Defense (DoD) Breast Cancer Research Program (BCRP), totaling nearly $16 million for breast cancer research. These BCRP-funded studies have produced many significant discoveries within his laboratory, contributing to Dr. Elledge's receipt of the Breakthrough Prize and significantly advancing the breast cancer research field.
As cells grow and divide, they must maintain and generate precise copies of their DNA. DNA damage resulting from a variety of intra- and extracellular insults, if not properly repaired, can permanently alter the genetic code and result in a multitude of negative effects, including cancer development and progression. Throughout the course of his career, Elledge has pioneered discoveries unraveling the DNA damage response, a group of signaling pathways utilized by cells to sense and repair damage to DNA. Proteins involved in the DNA damage response have been shown to be mutated or improperly regulated in breast cancer, including Brca1 and Brca2 (breast cancer 1 and 2). Germline mutations within the BRCA1 and BRCA2 genes are the strongest genetic risk factor for developing breast cancer, and reduced BRCA1 expression is observed in many breast tumors. Starting with a 1997 Idea Award, the BCRP funded several projects in Elledge's lab examining BRCA1 and Chk2 (checkpoint kinase 2), which were instrumental in elucidating the DNA damage response network.1-5 Elledge credits funding from the BCRP in the early years of his career for not only aiding his research into the DNA damage response but also in helping transition his laboratory from yeast-based to mammalian-based studies. This transition both broadened the scope of research within Elledge's laboratory and increased the clinical applicability of his studies.
Elledge is known for his inventive thinking and developing novel techniques to unravel the complex and interconnected cellular pathways that contribute to cancer. Promoting innovative and impactful research has been a driving force behind the types of award mechanisms offered by the BCRP. The award mechanism that most embodies this philosophy is the Innovator Award, which supports innovative, paradigm-shifting individuals and allows them to pursue their most high-risk ideas. Elledge was a 2003 recipient of the BCRP Innovator Award and two other Innovator expansion grants. According to Elledge, "The Innovator Awards have had the largest impact because they asked me to think outside of the box and gave me the support to follow through on these ideas. The BCRP has given me the freedom to take risks that NIH (National Institutes of Health) funding would never allow."
Elledge's Innovator Awards have resulted in a variety of outcomes that have made a major impact on the cancer research field. These awards led to the development of tools for performing genetic screens in mammalian cells. RNA interference (RNAi) is a cellular system that controls the activation or silencing of genes. Small hairpin RNAs (shRNAs) are one of the gene-silencing mechanisms of RNAi. In collaboration with another BCRP Innovator Award recipient, Dr. Greg Hannon, of CRUK Cambridge Institute, Elledge developed Expression ArrestTM shRNA libraries, which are whole-genome shRNA libraries that target over 30,000 genes.6 This commercially available research tool provides investigators with ready-to-use, rapid RNAi screens for the entire human and mouse genomes to study gene regulation and identify new therapeutic targets in many diseases and conditions, including cancer. Using this system, Elledge has performed a variety of genetic screens that have led to many important discoveries, including the identification of: (1) novel genes that suppress transformation of human mammary epithelial cells, including RE1-Silencing Transcription Factor (REST);7 (2) genes required for proliferation and survival in a variety of cancer cell lines;8 (3) genes that can be targeted to selectively kill cancer cells carrying mutations within the KRAS oncogene;9 and (4) genes and cancer gene islands that promote cell proliferation and are frequently deleted in breast cancer and other cancer types.10
The Innovator Award also shifted Elledge's current scientific interests towards immunology. This award, and its follow-on funding, led to the development of Phage Immunoprecipitation sequencing (PhIP-seq) technology, a high-throughput method for capturing and profiling targets of autoantibodies,11 which has the potential for the early detection of breast cancer. This work has also led to the recent development of VirScan, a novel medical test that utilizes the PhIP-seq technology to comprehensively profile a person's viral infection history using a single drop of blood.12
The BCRP continues to support novel, groundbreaking research within Elledge's laboratory. Elledge is the current recipient of a 2014 BCRP Breakthrough Award, examining the role of aging in the development of breast cancer. Age is one of the strongest risk factors for breast cancer due to a variety of factors, including increased mutational burden, decreased efficiency of the immune system, and alterations in the breast microenvironment. One of the key changes to the breast microenvironment is the accumulation of senescent cells. Senescence is a phenomenon where cells cease to divide yet continue to live in a permanently arrested state, due to DNA damage or activated oncogenes; senescent cells promote both aging and tumor growth. With support from the BCRP, Elledge is investigating how senescent cells promote breast cancer development.
In addition to being a recipient of BCRP funding, Elledge has also participated in the BCRP by serving as a grant reviewer. According to Elledge, "My experience with the BCRP certainly got me interested in breast cancer work, which has a natural connection to DNA repair, and had a huge impact on my research direction. Beyond that, the many people who support the BCRP program, especially the advocates, gave me a completely different and realistic perspective on the disease, and the urgency of working on it."
The BCRP is proud to congratulate Dr. Stephen Elledge on his Breakthrough Prize and the significant contributions he has made to the breast cancer research field.
References:
1 Cho RJ, Huang M, Campbell MJ, et al. 2001. Transcriptional regulation and function during the human cell cycle. Nat Genet 27:48-54.
2 Hirao A, Cheung A, Duncan G, et al. 2002. Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol Cell Biol 22(18):6521-6532.
3 Wang B, S Matsuoka, PB Carpenter, and SJ Elledge. 2002. 53BP1, a mediator of the DNA damage checkpoint. Science 298:1435-1438.
4 Lin Sy, K Li, GS Steward, and SJ Elledge. 2004. Human claspin works with BRCA1 to both positively and negatively regulate cell proliferation. Proc Natl Acad Sci U S A 101:6484-6489.
5 Morales JC, Xia Z, Lu T, et al. 2004. Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability. J Biol Chem 278:14971-14977.
6 Silva JM, Li MZ, Chang K, et al. 2005. Second generation shRNA libraries covering the mouse and human genomes. Nat Genet 37:1281-1288.
7 Westbrook TF, Martin ES, Schlabach MR, et al. 2005. A genetic screen for candidate tumor suppressors identifies REST. Cell 121:837-848.
8 Schlabach MR, Luo J, Solimini NL, et al. 2008. Cancer proliferation gene discovery through functional genomics. Science 319:620-624.
9 Luo J, Emanuele MJ, Li D, et al. 2009. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137(5):835-848.
10 Solimini NL, Xu Q, Mermel CH, et al. 2012 Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 337(6090):104-9.
11 Larman HB, Zhao Z, Laserson U, et al. 2011. Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol 29:535-541.
12 Xu GJ, Kula T, Xu Q, et al. 2015. Comprehensive serological profiling of human populations using a synthetic human virome. Science 348(6239):aaa0698.
Links:
Public and Technical Abstracts: The Role of KIP2 in Breast Cancer
Public and Technical Abstracts: Genomic Approaches for Detection and Treatment of Breast Cancer
Public and Technical Abstracts: Identification of Genes Required for the Survival of BRCA 1-/- Cells
Public and Technical Abstracts: DNA Repair Pathways as Targets for Treating Breast Cancer
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