Why Some Women with Breast Cancer Gene Don't Get Cancer

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A genetic test can reveal whether a woman has inherited the genes that make her more prone to developing breast cancer, but a positive result still will leave her wondering whether she actually will develop breast cancer. A new study may help further clarify a woman's risk.

If a woman has a harmful mutation in a BRCA gene (short for breast cancer susceptibility gene), the odds are 60 percent that she will develop breast cancer during her lifetime. There are two BRCA genes, BRCA1 and BRCA2, but BRCA1 is more strongly linked with cancers that are particularly hard to treat.

The new study showed that among women with mutations in their BRCA1 genes, those who also had mutations in another gene, called RHAMM, were slightly more likely to get cancer. On the other hand, those with BRCA1 mutations but no RHAMM mutations were less likely to get cancer.

The research also uncovered one role of BRCA1 in healthy cells: to help keep cell structures organized when a cell progresses from one stage of its life to the next. This discovery may point the way to future treatments, the study researchers say.

"This increases our knowledge of the molecular events that go on with hereditary breast cancer ," said Christopher Maxwell of the University of British Columbia in Vancouver, who is first author of the new paper.

The findings appear today (Nov. 15) in the journal Public Library of Science Biology.

The underpinnings of cancer

Maxwell, along with an international team of scientists, wanted to better understand how BRCA1 leads to the development of tumors .

"We thought there must be a unique genetic pathway related to these BRCA1 tumors," Maxwell said. "And we wanted to find it."

Here's what they found: Mutations in BRCA1 prevent cells from reorganizing when they progresses to a new stage in their life cycle. Instead, cells get stuck in a phase that promotes constant growth and division — the drivers of cancer.

Further, the study showed the proteins encoded by the BRCA1 and RHAMM genes interact with a third protein. When both BRCA1 and RHAMM are mutated, that third protein "wins" out more easily, further raising the chances the cell will get stuck in the dividing stage and become cancerous.

This third protein, nicknamed AURKA, could be targeted with existing treatments.

"Now that we know that, there are drugs that can block AURKA and may be able to drive the cells to differentiate, stopping them from forming a tumor," said Maxwell.

Many roles for one gene

Eva Turley, a biologist at the University of Western Ontario, discovered the RHAMM gene. She called the new findings "very intriguing" but said she doesn't think they explain the full story of RHAMM and BRCA1.

"Tumors are also influenced from the outside, by the microenvironment surrounding them," Turley said. Her lab and others have shown that RHAMM also has functions in controlling the environment outside of the cell.

The idea that cells' organization patterns play a role in cancer, Turley said, has been gaining weight. Revealing how this organization works can help scientists understand what drives some tumors to form, and perhaps help them discover ways to block them.

BRCA1 was discovered in 1994, "but the average patient hasn't seen a lot come out of that knowledge in terms of treatment," Turley said.

"This finding may point the way to functions of BRCA1 that could be therapeutic targets," she said.

Pass it on:  BRCA1, a gene that is linked to a woman's risk of breast cancer, contributes to a cell's overall structure and organization.

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