Even though men inherit the same mutant genes that women do, when it comes to hereditary breast cancer, men just don't get it. New research suggests why that may be. A mutation that leads to breast and ovarian cancer in women may unlock trouble in the second X chromosome, which is lacking in men.
About 5% to 10% of inherited breast and ovarian cancers are due to mutations in the BRCA1 gene, whose protein product normally repairs damaged DNA. Although men also carry these mutations, breast cancer in males is exceedingly rare. Previously, researchers had noticed that dividing cells in mouse testes produce a lot of BRCA1 messenger RNA. It so happens that the chromosomes in those cells are tightly packed, similar to one of the X chromosomes in women's cells. This packed chromosome in women is inactivated to prevent women from getting double the dose of the genes encoded on the X chromosome; a man's single X is never shut down.
To investigate whether BRCA1 helps inactivate the X chromosome in women, a team led by cancer biologist David Livingston at the Dana-Farber Cancer Institute in Boston examined noncancerous, cultured breast cells, using antibodies to mark BRCA1 and an RNA molecule known as XIST that coats and inactivates X chromosomes. Livingston and his colleagues found that the two molecules bound to each other and rested on the shutdown X chromosome. In tumor cells from five breast and ovarian cancer patients who lack BRCA1, however, they found no XIST coating either chromosome, suggesting that loss of BRCA1 might power up the second X. The researchers turned to cultured breast cancer cells lacking BRCA1 to determine the effect of restoring BRCA1. When they added BRCA1 to these cells, XIST once again encrusted the inactivated X, they report in the 1 November issue of Cell.
Cells without BRCA1 might be unable to inactivate the second X chromosome, speculates molecular biologist Robert Weinberg of the Massachusetts Institute of Technology in Cambridge. That might allow some gene products to be overproduced and perhaps contribute to cancer in women. "The finding was fully unexpected and stunning," he says.