By David N. Leff
"A riddle wrapped in a mystery inside a conundrum." That could describe the three baffling stages of breast cancer research.
Molecular biologists cracked much of the riddle five years ago when they nailed the two mutant genes - BRCA1 and BRCA2 - that account for the inherited 5 percent of mammary carcinoma patients. That finding led to genetic testing of non-symptomatic women in families prone to the disease.
It left open the mystery: What does that newly discovered BRCA1 gene (standing, of course, for "breast cancer") actually do in sickness and in health? What are the functions of the proteins it expresses?
Also left hanging is this conundrum: How do the 95 percent of sporadic (non-hereditary) breast cancer victims acquire their malignancy, if not from a gene?
"It may be that the entire mystery of how these problems with BRCA1 lead to cancer," observed biochemist Ramin Shiekhattar, at the Wistar Institute in Philadelphia, "can be explained by looking at how specific mutations interfere with the DNA control complex within which we find BRCA1." He is senior author of a progress report in the current issue of Cell, dated July 21, 2000, which goes a long way toward dispelling that mystery. Its title: "BRCA1 is associated with a human SWI/SNF-related complex: Linking chromatin remodeling to breast cancer."
"Once the gene-hunters identified those genes five years ago," Shiekhattar told BioWorld Today, "the major hindrance remained that the amino-acid sequences encoding the genes were very uninformative about what they do. So identifying what functions BRCA1 and 2 have was left to either a lot of genetic methods or to biochemical methods.
"The bottom line became to really try to get at the question in a biochemical way," he pointed out. "So we and a lot of other people tried to purify the BRCA1-containing complexes from human cells. And by identifying the associated proteins, try to resolve what their functions may be. That's what our paper in Cell is saying."
Getting A 'First' Into The Record
"To my knowledge," Shiekhattar pointed out, "this is really the first time that somebody has isolated the complex to near-homogeneity - meaning that this is really the first instance of a bona fide BRCA1-containing complex. And what was interesting," he went on, "is that almost all of the components we identified turned out to be part of a machinery that had been studied previously, called the SWI/SNF complex. It's involved in changing the structure of chromatin.
"DNA is wrapped around chromatin," Shiekhattar explained, "and chromatin is what actually packages the DNA helix. So in order to gain access to DNA you have to uncoil it. And molecular machinery such as SWI/SNF is involved in this kind of unpackaging. It's required for a number of cellular processes. SWI/SNF is intimately tied in to transcription, which is the expression of genes. Also, it may play a major role in DNA repair, because in order for the repair machinery to gain access to the DNA, this unpackaging has to occur first. So in essence this machinery works to unravel the chromatin to allow accessibility to different components of the transcription and DNA repair machinery.
"What we found," the Wistar biochemist went on, "was that BRCA1 made a direct contact to the engine driving this machinery. It's a protein called BRG1, expressed by a gene, BRG1, that in many respects is similar to BRCA1. I presume it would be an important candidate gene for breast and ovarian cancers.
"What's more," Shiekhattar continued, "there's a whole bunch of other mutations that perhaps result in what's now considered sporadic breast and ovarian cancers. They may be these other SWI/SNF subunits. There's a precedent for this," he recalled. "Another member of the SWI/SNF family, called SNF5 - a subunit of this complex - was recently shown to be involved in an aggressive pediatric cancer of soft tissue, such as brain or kidney. So I think that as we learn more about this complex, and its involvement in cancer, we will know that other subunits are intimately linked to hyperproliferation."
Shiekhattar then turned to the potential clinical payoffs of these findings. "To really understand what is going on," he observed, "we're going to have to have a concrete view of the molecular mechanism. Without that, we can't really think of the novel therapeutics that would target the precise mechanism these genes are functioning through. That BRCA1 is signaling its action through this SWI/SNF complex will definitely make this complex a target of therapeutics.
"A lot of drugs that are now used to treat cancer could as well be affecting SWI/SNF. We have already tested this hypothesis, and it is true. Many of these cancer chemotherapeutics affect this complex. But the problem is that most of these drugs are very general toxins, and affect anything that has to do with DNA. But down the road," he surmised, "I think that one can conceive of drugs that would get around this drawback.
"For example, BRG1 is an enzyme that hydrolyzes ATP to remodel chromatin. So if one can target, let's say, the BRG1 overactivity or ATPase inhibitors, one may be able to stop overproliferation."
Patent Pending, Licensure Open
"So I think what we found, clearly," Shiekhattar concluded, "is a first step in delineating this mechanism. We've also pointed out that a whole series of other components of this complex may be targets of mutations in other forms of breast and ovarian cancer. And we have also delineated this SWI/SNF complex as a possible target that drug companies might like to study in the future, and perhaps develop better drugs to specifically modulate this complex."
Wistar filed a U.S. patent application immediately in advance of the Cell publication, said the institute's director of business development, Meryle Melnicoff. It's headed, she told BioWorld Today, "Compositions and methods for cancer screening." She added, "Its sole inventor is Ramin Shiekhattar." She noted that the filing "covers the disclosure of BRCA1 interactions set forth in the paper," and concluded that "those technologies are now available for licensing." n