Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk

Abstract

Protein phosphatase 2A (PP2A) is a major cellular phosphatase and plays key regulatory roles in growth, differentiation, and apoptosis. Women who are diagnosed with benign proliferative breast disease are at increased risk for the subsequent development of breast cancer. The authors evaluated genetic variation of PP2A holoenzyme subunits for their potential contribution to breast cancer risk. A nested case-control investigation was performed on a cohort of women who had a history of benign breast disease. The women were followed for an average of 18 years, and DNA prepared from the original archival benign breast biopsy (1954-1995) was available for 450 women who were diagnosed with breast cancer on follow-up and for 890 of 900 women in a control group who were matched on race, age, and year of entry biopsy. Single allele-based and haplotype-based tests of association were conducted with assessment of significance by permutation testing. Significant risk and protective haplotypes of the PP2A structural/regulatory subunit A alpha isoform (PPP2R1A) were identified and had odds ratios of 1.63 (95% confidence interval [CI], 1.3-2.1) and 0.55 (95% CI, 0.41-0.76), respectively. These odds ratios remained significant after the analysis was adjusted for multiple comparisons. Women who had both the PPP2R1A risk haplotype and a history of proliferative breast disease had an odds ratio of 2.44 (95% CI, 1.7-3.5) for the subsequent development of breast cancer. The effects of haplotypes for 2 PP2A regulatory subunit genes, PP2 regulatory subunit B alpha isoform (PPP2R2A) and PP2A regulatory subunit B' epsilon isoform (PPP2R5E) on breast cancer risk were nominally significant but did not remain significant after the analysis was adjusted for multiple comparisons. The current findings supported the previously hypothesized role of PP2A as a tumor suppressor gene in breast cancer.