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No Association between the Progesterone Receptor Gene +331G/A Polymorphism and Breast Cancer

Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia

Requests for reprints: Heather Spencer Feigelson, Department of Epidemiology and Surveillance Research, American Cancer Society, 1599 Clifton Road NE, Atlanta GA 30309. Phone: 404-929-6815; Fax: 404-327-6450. E-mail: heather.feigelson{at}cancer.org

	Introduction

Top Introduction Methods Results and Conclusion References

 
Progesterone is critical to normal breast development, and its activity is mediated by the progesterone receptor (PR) that is part of the steroid-thyroid-retinoic acid receptor superfamily of transcription factors (1). A single copy of the progesterone receptor gene (PGR), located on chromosome 11q22-23, uses separate promoters and translation start sites to produce two protein isoforms, PR-A and PR-B, which are functionally distinct (2). Mouse models have demonstrated that PR-mediated signaling pathways are essential for carcinogen-induced mammary gland carcinogenesis and that mammary gland response to progesterone depends on the ratio of PR-A to PR-B (1).

DeVivo et al. (3) resequenced PGR and discovered a single nucleotide polymorphism (+331G/A) that altered transcriptional activity and favored production of PR-B in an endometrial cancer cell line. Further, they showed that this single nucleotide polymorphism was associated with increased risk of both endometrial cancer and breast cancer (3, 4). Given the strong biological evidence that this single nucleotide polymorphism may alter the PR-A to PR-B ratio, we sought to examine the association between PGR +331A/G in a nested case-control study of postmenopausal breast cancer.

	Methods

Top Introduction Methods Results and Conclusion References

 
Study Population
Women in this study are participants in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, a prospective study of cancer incidence including 184,000 U.S. adults. Participants completed a 10-page mailed questionnaire in 1992 that included information on demographics, diet, and other lifestyle factors. The recruitment and characteristics of this cohort are described in detail elsewhere (5). Follow-up questionnaires are sent to surviving cohort participants every 2 years beginning in 1997 to update exposure information and to ascertain occurrence of new cases of cancer. Incident cancers reported on the questionnaires are verified through medical records, linkage with state cancer registries, or death certificates.

From June 1998 to June 2001, blood samples were collected from a subgroup of 39,376 cohort members. After obtaining informed consent, a maximum of 43 mL of nonfasting whole blood was collected from each participant and separated into aliquots of serum, plasma, RBC, and buffy coat. Samples were frozen in liquid nitrogen vapor phase at approximately –130°C for long-term storage.

We selected 507 postmenopausal breast cancer cases diagnosed between 1992 and 2001 and 507 individually matched controls. We selected only cases and controls with no previous history of cancer (other than nonmelanoma skin cancer) at diagnosis date. Controls were matched on age (±6 months), race/ethnicity (White, African American, Hispanic, Asian, or other/unknown), and date of blood collection (±6 months). For all cases, exposure information was collected by questionnaire before the cancer diagnosis (i.e., in 1992); however, collection of blood samples occurred after cancer diagnosis or, in rare cases, slightly before cancer diagnosis.

Laboratory
DNA was extracted from buffy coat, and genotyping assays were performed using TaqMan (Applied Biosystems, Foster City, California) as described previously (4). Genotyping was performed by laboratory personnel blinded to case-control status, and 10% blind duplicates were randomly interspersed with the case-control samples to validate genotyping procedures. Concordance for the quality control samples was 100%. Overall success rate for the genotyping assays was 96%. The genotype distribution was in Hardy-Weinberg equilibrium.

Statistical Analysis
Unconditional logistic regression, Fisher's exact tests, and ² tests were used to examine the association between the +331A allele and breast cancer while controlling for matching factors and other possible confounders. Effect modification of the association between breast cancer and +331 genotype by body mass index (BMI) and hormone replacement therapy (HRT) use was also examined by stratified analysis and logistic regression.

	Results and Conclusion

Top Introduction Methods Results and Conclusion References

 
Genotyping data were missing on 28 (5.5%) cases and 13 (2.6%) controls. Cases and controls were largely White (99%), with median age of 62 years (range 43 to 75) at enrollment (in 1992). Table 1 shows the genotype frequencies, odds ratios (OR), and 95% confidence intervals (CI) for the association between breast cancer and the +331A allele. The +331 genotype did not differ among cases and controls (Fisher's exact P = 0.76). Because the A allele is rare (frequency among controls = 5%), logistic regression models compare the +331G/G with the G/A and A/A genotypes together. Including potential confounders in the logistic models in addition to the matching variables resulted in very little change in the effect estimates or CIs.

We found no association between the +331G/A single nucleotide polymorphism and breast cancer. Our results do not support the recent findings of DeVivo et al. who have reported that the +331A allele is associated with increased risk of both breast (4) and endometrial (3) cancers.

The primary limitation of this study is limited statistical power to detect a weak association given the low frequency of the risk genotype (10%). When = 0.05, ß = 0.20, and the observed genotype frequency among controls, our study had sufficient power to detect a minimum OR of 1.7. Under the same assumptions, a sample size of 5,000 cases and 5,000 controls would be required to detect an OR of 1.20.

Given the evidence from animal studies that PR is an important regulator of mammary growth and development and further that an imbalance of the ratio between the two PR isoforms may lead to disruption of normal growth and differentiation of mammary cells, further study of the role of PR variation and breast cancer is warranted.

	Acknowledgments

 
We thank Dr. Immaculata DeVivo (Channing Laboratory, Harvard Medical School) for providing scientific expertise and supervision of the genotyping.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/ 5/03; accepted 2/ 2/04.

	References

Top Introduction Methods Results and Conclusion References

 

1. Gao X, Nawaz Z. Progesterone receptors—animal models and cell signaling in breast cancer: role of steroid receptor coactivators and corepressors of progesterone receptors in breast cancer. Breast Cancer Res 2002;4:182-6.[CrossRef][Medline]
2. Mulac-Jericevic B, Mullinax RA, DeMayo FJ, Lydon JP, Conneely OM. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 2000;289:1751-4.[Abstract/Free Full Text]
3. DeVivo I, Huggins G, Hankinson S, et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci 2002;99:12263-8.[Abstract/Free Full Text]
4. DeVivo I, Hankinson S, Colditz G, Hunter D. A functional polymorphism in the progesterone receptor gene is associated with an increase in breast cancer risk. Cancer Res 2003;63:5236-8.[Abstract/Free Full Text]
5. Calle EE, Rodriguez C, Jacobs EJ, et al. The American Cancer Society Nutrition Cohort: rationale, study design and baseline characteristics. Cancer 2002;94:2490-501.[CrossRef][Medline]

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