In the Nov. 3, 2006, issue of Cell, researchers from Harvard Medical School and the Dana Farber Cancer Institute shed some light on why mutated copies of the BRCA1 gene dramatically raise the risk of breast or ovarian cancer for their unfortunate owners.

BRCA1 is known to participate in several cellular functions including the repair of double-stranded DNA breaks. In addition, it appears that BRCA1 and its cellular dance partner, BARD1, also influence a basic step in cell division: the formation of structures that separate duplicated DNA strands during cell division, preventing sibling rivalry by ensuring each daughter cell gets her fair share.

The researchers used both cultured cell lines and a cell-free system derived from eggs of the frog Xenopus laevis to investigate BRCA1's role in cell division, and found that "BRCA1 specifically interacts with spindle-pole organizing proteins," first author Vladimir Joukov, instructor in medicine at the Dana-Farber Cancer Institute, told BioWorld Today. The scientists found that the BRCA1/BARD1 complex is required specifically for the accumulation of TPX-2, a major spindle organizer.

TPX-2 in turn regulates two other proteins that already have come to the attention of cancer researchers: RHAMM and Aurora A kinase. "TPX-2, RHAMM and Aurora A are all either oncoproteins or candidate oncoproteins," Joukov said. So the findings connect the tumor suppressor BRCA1 with "three other proteins that have been implicated in cancer in their own right."

BRCA1's universal role in cell division is somewhat at odds with the fact that loss of the protein specifically raises the risk for breast and ovarian cancers. In fact, Joukov said, BRCA's evolutionary conservation was a surprise when it was first discovered. "There is no breast in non-mammals," he explained. "So this was supposed to be a bonafide mammalian protein. But then unexpectedly, we found a homologue in arabidopsis" - definitely not a mammalian plant.

Further searching revealed that any number of organisms have BRCA1 homologues - but studying them proved tricky, since most cells lacking BRCA1 die off without further ado. That's where the Xenopus-derived model system came in handy.

"It's the best system to study the biochemical function of biological molecules," Joukov declared. "It is like a solution in which all the processes that normally occur in cells take place."

Of course, because proteins are not sequestered from each other in that solution, processes that normally do not occur in cells also can take place. Joukov acknowledged that discoveries made in Xenopus ultimately need to be road-tested in cells - as he and his colleagues did in the studies they report in Cell - but also noted that the proof has been in the pudding: "Many major discoveries concerning proteins of the cell cycle, and DNA replication, were first made in the Xenopus system. So it's a proven system."

Joukov and his colleagues next plan to investigate the exact mechanisms by which BRCA1 interacts with the spindle-forming proteins; BRCA1 itself can ubiquitinate proteins, and its exact target during cell division is of obvious interest for possible therapeutic targeting.

As for why BRCA1 specifically raises the risk for breast and ovarian cancer, the mechanisms are unclear, but Joukov said that "only breast and ovarian cells are able to survive without BRCA1 at all."

Other cell types, once they lose BRCA1, die off altogether rather than going into uncontrolled growth mode. That implies that therapeutic targeting could have at least two different goals: either to bring cell division back under control in cells that have lost BRCA1, or to somehow manipulate cells into instituting cell-cycle checkpoints that would kill breast and ovarian cells with BRCA1 mutations off altogether, as other cell types do.

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