Prohibitin T Allele Genotype Linked to Familial Breast Cancer

ORLANDO—Women with a specific prohibitin fragment genotype (T allele) and a first-degree relative with breast cancer appear to be at greater risk of developing the disease than women with the prohibitin C allele genotype, reported Eldon R. Jupe, PhD, senior research scientist, Immunology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City.

"It may be possible to use this in the future to help women with first-degree relatives with breast cancer assess their own risk of disease," he said at the Era of Hope Department of Defense Breast Cancer Research Program meeting.

The research team’s early work showed that prohibitin 3´untranslated region (3´UTR) is able to arrest cell cycle progression in normal mammary epithelial cells and breast-cancer cell lines. They discovered a 3´UTR single nucleotide polymorphism that defines two human prohibitin alleles—C and T—resulting in three genotypes: C/C, C/T, and T/T.

The C allele codes for a regulatory RNA that inhibits cancer cell growth while the T allele is inactive. Of the three genotypes, T/T occurs less frequently, in less than 3% of the general population. The T allele includes the C/T and T/T genotypes.

"A single C to T change in prohibitin 3´UTR is enough to inactivate the antiproliferative activity of this transcript," Dr. Jupe said. "Our hypothesis that originated out of this basic research was that carriers of the prohibitin T allele have an increased susceptibility to breast cancer."

Case-Control Study

The team conducted a case-control study to test the theory. They compared the prohibitin 3´UTR genotypes of 205 women with breast cancer with those of 1,046 cancer-free women. The women were consecutively enrolled patients having mammography at the University of Oklahoma Institute for Breast Health. The women self-reported any family history of breast cancer. Dr. Jupe presented an interim analysis of the results at the meeting.

"Overall, the association of the T allele with breast cancer is not particularly outstanding. The odds ratio is 1.3 and the P value is not significant," he said. "However, when we stratify by family history, looking at individuals who reported a first-degree relative with breast cancer, the odds ratio goes up to 2.5 and the P value is a significant .005."

Furthermore, among the breast cancer patients with a first-degree relative, those age 50 or less at onset of the disease were more likely to carry the T allele (odds ratio 4.8, P = .003). Among these women over age 50 at disease onset, the odds ratio for the T allele was 1.6. The mean age of disease onset of T allele carriers with first-degree relatives was 52 vs 59 for noncarriers. The median age of onset was 50 vs 60.

"In conclusion, it appears the prohibi-tin 3´UTR RNA that is encoded by the C allele arrests cell proliferation and suppresses tumor formation; however, the product of the T allele is not active," Dr. Jupe said. "Prohibitin genotyping may have value in assessing the risk of breast cancer in women age 50 or younger who report at least one first-degree relative with the disease."

Enrollment in the study continues, with a goal of 400 recently diagnosed breast cancer patients. The Department of Defense has funded the team for 4 years (with 3 remaining) to validate the results in a new study group.