Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

Study Proposes New Ovarian Cancer Targets

Published: Friday, March 14, 2014
Last Updated: Friday, March 14, 2014
Bookmark and Share
Researchers from Brown University propose that TAFs may be important suspects in the progression of ovarian cancer.

In the complex genomic and molecular conspiracy that gives rise to ovarian cancer, what if researchers have been missing a whole set of suspects because they’ve been hiding in plain sight? That’s the argument made by Brown University biologists in a new paper that combines evidence from original research and prior studies to raise new suspicions about a set of proteins that assist in regulating gene expression.

Scientists need such new leads in their investigation of ovarian cancer, the most deadly reproductive cancer. Mortality has remained tragically steady since the last major therapeutic breakthrough came in the 1990s. Pursuing the evidence that these proteins may be involved could allow researchers to make new progress.

“There is just not a lot of headway being made in ovarian cancer,” said pathobiology graduate student Jennifer Ribeiro, lead author of the study online in Frontiers in Oncology. “This is a different perspective. It’s a high-risk but potentially high-reward scenario.”

Ribeiro’s proteins of interest are called TAFs. Traditionally biologists have seen them merely as cogs in a universal and generic system that enables enzymes to transcribe genes into RNA, said study senior author Richard Freiman, associate professor of medical science at Brown. But in the new paper he and Ribeiro propose that TAFs may not merely be going about their droning business as ovarian tumors go haywire. They may be meaningfully associated with the calamity.

Guilt by many associations?
An early hint of a link between TAFs and ovarian cancer emerged in a 2011 Nature paper, coauthored by Brown University computer science researchers. Ribeiro followed up on that tip to make some of her main original findings in the new paper. By poring over the cBioPortal database of cancer genomics, she found that several TAFs are often significantly overexpressed or underexpressed in ovarian cancer. TAF2 amplifications, copy number gains, and expression increases are present in 73 percent of tumors. TAF4 is amplified or upregulated in 66 percent of tumors, and TAF4B is amplified or upregulated in 26 percent. TAF9, meanwhile, is rendered significantly less expressed in 98 percent of ovarian tumors.

The ups and downs of TAF expression alone might not be that interesting if TAF activity didn’t have any mechanistic influence in cancer cell biology. But in her review of scores of studies and further original research, Ribeiro presents reasons to believe that in specific tissues and contexts around the body, these TAFs take on roles that are relevant.

“They are not just general transcription factors,” Freiman said. “They do much more specific things.”

The worst tumors are ones in which cells have “dedifferentiated,” which means they’ve lost their specific identities and reverted to a more generic, stem cell-like form. Sure enough, Ribeiro and Freiman have found that TAFs such as TAF4 and TAF4B are downregulated when stem cells differentiate. That makes their upregulation in ovarian tumors suspicious.

TAF4B also emerges as a cancer suspect in the study because of its apparent role in promoting cell proliferation, a major problem in the runaway cell multiplication in tumors. Lindsay Lovasco, a postdoctoral fellow at Brown and second author of the study, ran an experiment in mouse models where she removed some of the liver and measured whether TAFs expression changed while the tissue regenerated. Expression of Taf4b (the gene in mice) did increase significantly. Also, in human ovarian granulosa cell-derived tumors, in collaboration with Dr. Barbara Vanderhyden at the University of Ottawa, Ribeiro found that TAF4B expression correlates strongly with Cyclin D2 expression, a protein that specifically promotes granulosa cell proliferation.

Even more suspicion falls on TAF4B based on Ribeiro’s finding published last year in Biology of Reproduction that estrogen upregulates the protein in mouse ovaries and in estrogen-supplemented mouse ovarian tumors. In humans, long-term estrogen hormone replacement therapy has been associated with a greater risk of ovarian cancer.

Cell growth and death
Meanwhile, TAF2 may have its own cancer-related modus operandi. Work by other researchers has shown that TAF2 boosts the expression of a protein called C-SRC, that promotes cell growth and proliferation. Perhaps not surprisingly, other studies have found that C-SRC is overexpressed in ovarian tumors.

“Given these results, it is possible that TAF2 overexpression could increase transcription of C-SRC in some ovarian tumors,” the researchers wrote.

But what of TAF9, which unlike its brethren seems to become notably less expressed in ovarian cancers? There, too, there is a suspicious mechanistic connection to ovarian cancer. TAF9 is a co-activator of the protein p53, which promotes cell death, a handy thing to promote in tumors. But p53 activity is also suppressed in ovarian cancer. Together, these changes may help ensure the survival of ovarian cancer cells.

Ribeiro and Freiman readily acknowledge that the case they build is circumstantial, but they argue it is more than enough for cancer researchers to look at TAFs as potential targets in their search for new treatments.

“We’ve compiled this hypothesis and provided the data that we think is relevant, but there still is much that is not known about it,” Ribeiro said.

In the lab now, Ribeiro and Freiman are testing the effects in human ovarian cancer cells of manipulating TAF expression and function.

The American Cancer Society (grant DMC-117629) and the National Institutes of Health (grant RO1HD065445) and the Canadian Institutes of Health Research Grant (grant MOP-111194 supported the research.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Web App Helps Researchers Explore Cancer Genetics
Brown University computer scientists have developed a new interactive tool to help researchers and clinicians explore the genetic underpinnings of cancer.
Monday, July 27, 2015
Scientific News
Revolutionary Technologies Developed to Improve Outcomes for Lung Cancer Patients
Breath test to detect lung cancer brings oxygen directly to the wound.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Mathematical Model Forecasts the Path of Breast Cancer
Chances of survival depend on which organs breast cancer tumors colonize first.
Exploring the Causes of Cancer
Queen's research to understand the regulation of a cell surface protein involved in cancer.
Nanocarriers May Carry New Hope for Brain Cancer Therapy
Berkeley lab researchers develop nanoparticles that can carry therapeutics across the brain blood barrier.
RNA-Based Drugs Give More Control Over Gene Editing
CRISPR/Cas9 gene editing technique can be transiently activated and inactivated using RNA-based drugs, giving researchers more precise control in correcting and inactivating genes.
University of Glasgow Researchers Make An Impact in 60 Seconds
Early-career researchers were invited to submit an engaging, dynamic and compelling 60 second video illuminating an aspect of their research.
Metabolic Profiles Distinguish Early Stage Ovarian Cancer with Unprecedented Accuracy
Studying blood serum compounds of different molecular weights has led scientists to a set of biomarkers that may enable development of a highly accurate screening test for early-stage ovarian cancer.
Dead Bacteria to Kill Colorectal Cancer
Scientists from Nanyang Technological University (NTU Singapore) have successfully used dead bacteria to kill colorectal cancer cells.
CRISPR-Cas9 Gene Editing: Check Three Times, Cut Once
Two new studies from UC Berkeley should give scientists who use CRISPR-Cas9 for genome engineering greater confidence that they won’t inadvertently edit the wrong DNA.

SELECTBIO Market Reports
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos