Findings Could Lead to New Therapies for Breast, Ovarian & Other Cancers
Inhibiting the action of a particular enzyme dramatically slows the growth of tumor cells tied to BRCA1 and BRCA2 genetic mutations which, in turn, are closely tied to breast and ovarian cancers, according to researchers at 嘿嘿视频 Medical Center.
Senior investigator and 嘿嘿视频 cell biologist Agnel Sfeir, PhD, says that if further experiments prove successful, these findings could lead to a new class of targeted therapies against cancers with BRCA1 and BRCA2 mutations. The researchers鈥 findings in experiments in mice and human cells are .
Dr. Sfeir and her collaborators say their discovery about the enzyme鈥攃alled polymerase theta, or PolQ鈥攔esulted from efforts to answer a fundamental biological question: How do cells prevent the telomere ends of linear chromosomes, which house our genetic material, from sticking together? Cell DNA repair mechanisms can stitch together telomeres broken as part of cell metabolism. But such fusions, the researchers say, compromise normal cell growth and survival.
鈥淚n the purest biological sense, our findings show how this particular enzyme, which we know is active in several tumors, promotes unwanted telomere fusions by inserting whole segments of DNA via a disruptive DNA repair pathway termed alt-NHEJ,鈥 says Dr. Sfeir, an assistant professor at 嘿嘿视频 and its Skirball Institute for Biomolecular Medicine and a member of 嘿嘿视频鈥檚 Laura and Isaac Perlmutter Cancer Center. 鈥淚t was quite remarkable to find that by blocking PolQ action, cancer cell growth was cut by more than half.鈥
For the study, Dr. Sfeir and colleagues at the Scripps Research Institute focused their analysis on telomeric DNA. They noted that as the chromosome ends were being joined, whole sections of new genetic material were being inserted into the telomeric DNA鈥攕uggesting that any of a dozen or more DNA-synthesizing polymerase enzymes were at work. Researchers then focused on PolQ, in part because it is known to be active in several tumors, including breast and ovarian, but also in liver and colon cancers. Breast and ovarian cancers are among the leading causes of cancer death among women in the United States.
Additional experiments confirmed that PolQ is needed to activate the alt-NHEJ pathway of DNA repair. Unlike the main, error-free pathway鈥攐r HDR pathway鈥攖he alt-NHEJ pathway does not use a related chromosome鈥檚 genetic material as a template to meticulously correct any damaged genetic material. As such, alt-NHEJ is highly likely to leave coding mistakes.
鈥淥ur studies will continue to look at how the alt-NHEJ pathway operates,鈥 Dr. Sfeir adds, 鈥渁nd what biological factors cells use in addition to PolQ to choose between the error-prone or error-free DNA repair pathways.鈥
Funding support for the study was provided by the Breast Cancer Alliance, the V-Foundation, the U.S. Department of Defense Breast Cancer Research Program, a Pew Scholars Award, the Novartis Advanced Discovery Institute, National Institutes of Health grant AG0386677, the Helen L. and Martin S. Kimmel Center for Stem Cell Biology, as well the University of Texas at Austin, and from the Cancer Prevention Research Institute of Texas.
Besides Dr. Sfeir, other researchers involved in this study were lead investigator Pedro Mateos-Gomez, PhD, also at 嘿嘿视频; Fade Gong, PhD, and Kyle Miller, PhD, at the University of Texas at Austin; and Eros Lazzerini-Denchi, PhD, at the Scripps Research Institute in La Jolla, Calif.
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