Association of the Alu insertion polymorphism in the progesterone receptor gene with breast cancer in a Mexican population

Abstract

Introduction: The progesterone receptor (PR) gene plays an important role in reproduction-related events. Data on polymorphisms in the PR gene have revealed associations with cancer, particularly for the Alu insertion polymorphism, which has been suggested to affect progesterone receptor function and contribute to tumor promotion in the mammary gland.

Material and methods: We examined the role of the Alu insertion polymorphism in the PR gene by comparing the genotypes of 209 healthy Mexican women with those of 481 Mexican women with breast cancer (BC).

Results: The genotype frequencies observed in the controls and BC patients were 0% and 4% for T2/T2 (Alu insertion), 16% and 21% for T1/T2, and 84% and 75% for T1/T1 (Alu deletion), respectively. The obtained odds ratio (OR) was 1.7, with a 95% confidence interval (95% CI) of 1.1-2.6, p = 0.009, for the T1/T2-T2/T2 genotypes. The association was also evident when the distributions of the T1/T2-T2/T2 genotypes in patients in the following categories were compared: obesity grade II (OR = 1.81, 95% CI: 1.03-3.18, p = 0.039) and the chemotherapy response (OR = 1.91, 95% CI: 1.27-3.067, p = 0.002).

Conclusions: The T1/T2-T2/T2 genotypes of the Alu insertion polymorphism in the PR gene are associated with BC susceptibility in the analyzed Mexican population.

Keywords: Mexican population; PROGINS; breast cancer; polymorphism; progesterone receptor.

Figure 1

The human PR gene contains eight coding exons and seven non-coding introns (A-G) encoding the PR-A and PR-B isoforms. The PR-A isoform is identical to PR-B, except that the PR-B isoform exhibits 165 amino acids in the amino-terminal region that form the third transactivation domain (AF-3). Exon 1 and part of 2 encode the A/B region, which contains the PR-B-specific transactivation domain AF-3, while AF-1 is found in both PR-B and PR-A. The inhibitory domain (ID) region is PR-A specific. The C region forms the DNA-binding domain (DBD); each of exons 2 and 3 encodes one zinc finger. The D region is encoded by exon 4 and part of exon 3 and forms the hinge region responsible for the nuclear location signal. The E region is encoded by exons 4 to 8 and contains AF-2 and the hormone (ligand)-binding domain. PR-C lacks the DBD, AF-3 and AF-1 regions. An amino-terminally deleted PR protein is predicted to result from the alternative initiation of translation at a methionine at position 595. The Alu insertion polymorphism interferes specifically with the PR-A isoform [14, 39]

Figure 2

Polyacrylamide gel 6% (29.1 : 1) silver nitrate stained. Gel. Lines 1, 4, 7, 8 homozygous T1T1 (178 bp); lines 2 and 6 heterozygous T1/T2 (178 and 479 bp); line 3 homozygous T2T2 (479 pb) and line 5 ladder (50 bp)