A decade ago, the hunt for the elusive breast cancer gene was in full swing. Scientists predicted that its imminent discovery would shed light on the origins of breast cancer not only for women who inherit a mutant gene, but for the thousands more who are diagnosed each year with noninherited forms of breast cancer.
Mary-Claire King, Ph.D., was then at the University of California at Berkeley, performing family studies that narrowed the search to a small region on chromosome 17. BRCA1 was finally cloned in 1994 by a group led by University of Utah scientists and was followed the next year by a second susceptibility gene, BRCA2. But after years of intense scrutiny, these genes have produced little insight into the workings of breast canceror for that matter, ovarian cancer, also associated with BRCA1. Instead, they have raised new puzzles and paradoxes.
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"The big, big puzzle of BRCA1 is why is it breast- and ovarian-specific, when everything weve been assigning for BRCA1 function happens in every single cell in the body," said Jeffrey D. Parvin, M.D., Ph.D., associate professor of pathology at Brigham and Womens Hospital and Harvard Medical School, Boston. Parvin and colleagues are working to define the proteins role in transcription, using biochemical methods to identify protein complexes it participates in.
"BRCA1 hasnt met a protein it doesnt like to interact withits a really sticky protein," he added. This stickiness poses a problem for researchers: not only must they demonstrate that BRCA1 associates with another protein, but they must explain why this particular interaction is significant. But it may eventually turn out to be a clue to the proteins function, he noted.
All evidence points to a central role of BRCA1 in maintaining genomic stabilityensuring that the genetic information carried in DNA is faithfully preserved through many cycles of cell division. The protein is crucial from the first days of an organisms existence: knockout mice lacking functional BRCA1 die after a few days in utero.
"BRCA1 and BRCA2 are required for a normal proliferative burst in early embryogenesis . . . and are upregulated with proliferation of breast epithelial cells during puberty, pregnancy, and lactation," Welcsh, King, and colleague Kelly N. Owens, Ph.D., wrote in the February 2000 Trends in Genetics. "This role is paradoxical, given that in adult breast or ovarian epithelium, loss of BRCA1 or BRCA2 leads to tumorigenesis."
Scientists have uncovered several distinct functions for BRCA1 that may solve the paradox, explaining how its loss could lead to cancer. There is abundant evidence that the protein participates in the control of cell cycle checkpoints and the repair of DNA damage, said Wen-Hwa Lee, Ph.D., chairman of the Department of Molecular Medicine at the University of Texas Health Science Center, San Antonio. In its checkpoint control role, BRCA1 acts as a transcriptional co-activator and co-repressor, turning the production of other genes on and off.
Earlier this year, a group of Japanese researchers showed that BRCA1 and molecular partner BARD1a protein identified via its association with BRCA1can effectively collaborate in ubiquitination, a process in which proteins are tagged for destruction once their work is finished. But the researchers did not define the targets of BRCA1/BARD1 ubiquitination.
In the May 22 Proceedings of the National Academy of Sciences, Tanya Paull, Ph.D., and colleagues at the University of Texas, Austin, show that BRCA1 directly binds DNA and preferentially binds to four-way branched DNA structures, which appear only during replication and repair. This finding strengthens the case that BRCA1 is directly involved in DNA repair.
In the same issue of PNAS, Parvin synthesizes this and other data into a model that attempts to integrate BRCA1s various functions. A key earlier finding, to which Parvin and colleagues contributed, is that BRCA1 and BARD1 are components of the mRNA synthesizing machine called the Pol II holoenzyme complex.
Parvin proposes that the Pol II complex halts at the site of DNA damage, where it is taggedubiquitinatedby BRCA1 and BARD1, then degraded, thus stopping transcription. BRCA1 is left bound to the damaged DNA, where it recruits other proteins (such as Rad 51, a known repair factor and BRCA1 associate) to perform the fix.
In a cell missing BRCA1, damage would go unrepaired. Most such cells would be swiftly dispatched by apoptosis. But if the damage included a disabling mutation in a gene such as p53 that guards genomic integrity, the cell might escape death and go on to uncontrolled proliferation.
But why does this happen only in the breast and ovary? Despite the early surprise that the long-sought breast cancer gene was not clearly associated with estrogen, the hormones possible role remains a major topic of interest. Some investigators have speculated that BRCA1 protects against the carcinogenic effect of estrogen itself. Another possibility is that BRCA1 regulates estrogen signaling pathways.
In 1999, Eliot M. Rosen, M.D., Ph.D., and colleagues at Albert Einstein College of Medicine in New York found that BRCA1 inhibits estrogen receptor signaling. New evidence to strengthen the estrogen connection comes from a study now in press, in which Wen-Hwa Lee, with departmental colleague Thomas G. Boyer, Ph.D., and co-authors show that BRCA1 represses transcription of the estrogen receptor independent of estrogen.
"Our findings suggest that BRCA1 may be acting as a brake on the estrogen receptor when estrogen is not around," and that inactivation of BRCA1 could promote tumorigenesis through inappropriate hormonal responses, Boyer said.
Another reason breast tissue may be particularly vulnerable is that cells produced during bursts of rapid proliferation remain in the breast, in contrast to other kinds of epithelial cellsin the gut or endometrium, for examplethat proliferate rapidly but are continually sloughed off.
In the April 1 Human Molecular Genetics, Welcsh and King offer an explanation for another puzzle: why are BRCA1 mutations so rarely found in noninherited breast cancer cases? In fact, they note, a very high proportion of these sporadic tumors do show loss of at least one BRCA1 allele.
The gene and its surrounding region on chromosome 17 have an unusually high proportion of elements called Alu repeats. These repetitive sequences greatly increase the likelihood that an error will occur during DNA synthesis and that a loose end will be reattached to an identical strand far along the molecule, mistakenly cutting off a loop of DNA. The result: a deletion of the whole gene or a large portion of it.
"When people didnt find [point] mutations in sporadic tumors, they concluded that BRCA1 isnt involved in sporadic tumorigenesis as we had hoped," Welcsh said. Instead, "were seeing very large regions of the gene that are lostusually the entire gene."
Deletions caused by Alu repeats are probably very common, and BRCA1 appears to be inactivated in a variety of other ways at the RNA and protein levels, Welcsh and King argue. "At the DNA level, at the message [RNA] level, and at the protein level, the evidence indicates theres something going on with BRCA1 in sporadic breast tumors," Welcsh said. However, two "hits," knocking out both copies would take longer to occur in "wild-type" women than in women who are born with a mutated copyhence the difference in age of onset.
Like much else in biology, the BRCA1 story is more complex, and is taking longer to unravel, than many had initially hoped.
"People were looking for a magic bullet . . . but the expectation of a short-term fix was misguided, as it turned out," Parvin concluded. "We have to think long term. We have to hit the labs hard to find out what its doing functionally, and how we can intervene in that process."
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