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

Gallegos-Arreola MP, Figuera LE, Flores-Ramos LG, Puebla-Pérez AM, Zúñiga-González GM - Arch Med Sci (2015)

Bottom Line: The progesterone receptor (PR) gene plays an important role in reproduction-related events.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).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.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética Molecular, División de Medicina Molecular, Centro de Investigación Biomédica de Occidente (CIBO), Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México.

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.

No MeSH data available.


Related in: MedlinePlus

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]
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Figure 0001: 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]

Mentions: The human progesterone receptor (PR) gene, which is located on chromosome 11q22-23, comprises eight exons and seven introns (A–G). This gene encodes two isoforms, which are identical except for 165 additional amino acids found at the N-terminus of the B isoform. These isoforms regulate the biological action of progesterone: isoform A inhibits activation of the PR, while isoform B activates it [10, 11]. The PR gene exhibits several reported polymorphisms, one of which is designated the PROGINS haplotype and includes an Alu insertion in intron G, a G/T substitution in exon 4 (rs1042838), and a silent C/T substitution in exon 5 (rs1042839). These PROGINS polymorphisms are in complete linkage disequilibrium (Figure 1) [12]. The Alu polymorphism consists of a 306 bp insertion in the G intron located between exons 7 and 8 of isoform A of the PR gene in humans [13]. Although the biological impact of the Alu insertion polymorphism is not clear, it has been suggested that it might lead to aberrant gene transcription, resulting in an inability of the hormone receptor to bind progesterone and subsequently become activated, with a consequent reduction of the activity mediated by progesterone. Progesterone participates in the regulation of gene expression and affects cellular proliferation and differentiation in its target tissues. Therefore, PR gene deficiency may have a potential impact on oncogenesis [14].


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

Gallegos-Arreola MP, Figuera LE, Flores-Ramos LG, Puebla-Pérez AM, Zúñiga-González GM - Arch Med Sci (2015)

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]
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495151&req=5

Figure 0001: 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]
Mentions: The human progesterone receptor (PR) gene, which is located on chromosome 11q22-23, comprises eight exons and seven introns (A–G). This gene encodes two isoforms, which are identical except for 165 additional amino acids found at the N-terminus of the B isoform. These isoforms regulate the biological action of progesterone: isoform A inhibits activation of the PR, while isoform B activates it [10, 11]. The PR gene exhibits several reported polymorphisms, one of which is designated the PROGINS haplotype and includes an Alu insertion in intron G, a G/T substitution in exon 4 (rs1042838), and a silent C/T substitution in exon 5 (rs1042839). These PROGINS polymorphisms are in complete linkage disequilibrium (Figure 1) [12]. The Alu polymorphism consists of a 306 bp insertion in the G intron located between exons 7 and 8 of isoform A of the PR gene in humans [13]. Although the biological impact of the Alu insertion polymorphism is not clear, it has been suggested that it might lead to aberrant gene transcription, resulting in an inability of the hormone receptor to bind progesterone and subsequently become activated, with a consequent reduction of the activity mediated by progesterone. Progesterone participates in the regulation of gene expression and affects cellular proliferation and differentiation in its target tissues. Therefore, PR gene deficiency may have a potential impact on oncogenesis [14].

Bottom Line: The progesterone receptor (PR) gene plays an important role in reproduction-related events.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).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.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética Molecular, División de Medicina Molecular, Centro de Investigación Biomédica de Occidente (CIBO), Centro Médico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, México.

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.

No MeSH data available.


Related in: MedlinePlus