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[Cancer Research 63, 5236-5238, September 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

A Functional Polymorphism in the Progesterone Receptor Gene Is Associated with an Increase in Breast Cancer Risk1

Immaculata De Vivo2, Susan E. Hankinson, Graham A. Colditz and David J. Hunter

Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School [I. D., S. E. H., G. A. C., D. J. H.], and Departments of Epidemiology [I. D., S. E. H., G. A. C., D. J. H.], Nutrition [D. J. H.], and Harvard Center for Cancer Prevention [I. D., D. J. H., G. A. C.], Harvard School of Public Health, Boston, Massachusetts 02115


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Biological and epidemiological data suggest that progesterone has an important role in mammary tumorigenesis. Because the effects of progesterone require the progesterone receptor (PGR), which exists in two isoforms, PR-A and PR-B, we sought to determine whether the functional polymorphism, +331 G/A, which causes an increase in the expression of the hPR-B isoform, is related to breast cancer risk. Using a nested case-control study design within the Nurses’ Health Study cohort, we genotyped 990 cases and 1,364 controls and observed a statistically significant increased risk of breast cancer among carriers of the +331 A allele (odds ratio, 1.33; 95% confidence interval, 1.01–1.74) compared with subjects with the GG genotype. We also observed a potential interaction between genotype and body mass index (BMI) among postmenopausal women, with the highest risk (odds ratio, 2.30; 95% confidence interval, 1.02–5.21) among obese women (BMI >=30 kg/m2) with the GA or AA genotype compared with lean (BMI <25 kg/m2) women with the GG genotype. Our findings suggest that the increased production of hPR-B by the +331 G/A polymorphism may predispose women to breast cancer development through increased hPR-B-dependent stimulation of mammary cell growth.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Progesterone and estrogen are the main steroid hormones involved in normal breast development and tumorigenesis (1) . Although the proliferative effects of estrogen on mammary gland development and tumorigenesis are well recognized, the contribution of progesterone to these processes is less well understood. Evidence from epidemiological studies has shown that early onset of menarche, late menopause, nulliparity, a late first birth and reproductive states that are affected by the absence or presence of progesterone, increase a woman’s risk for breast cancer. More recently, data from epidemiological studies revealed a higher risk of breast cancer in postmenopausal women who used a combination of estrogens and progestins, as compared with those women who used estrogens alone (2 , 3) .

As demonstrated in PRKO3 mice, the physiological effects of progesterone are completely dependent on the presence of the human PGR, a member of the steroid-receptor superfamily of nuclear receptors (4) . The single-copy PGR gene, located on chromosome 11q22–23, uses separate promoters and translational start sites to produce two protein isoforms, hPR-A and hPR-B (5, 6, 7) , that are identical except for an additional 165 amino acids present only in the NH2 terminus of hPR-B (8 , 9) . Although hPR-B shares many important structural domains with hPR-A, the two isoforms are functionally distinct transcription factors (10) that mediate their own response genes and physiological effects with little overlap (11 , 12) . The PRKO mouse, in which the functional activity of both hPR-A and hPR-B were simultaneously ablated, revealed that progesterone is required for the formation of ductal and alveolar structures during pregnancy (4 , 13) . The PRKO mouse, when used in the context of an established carcinogen-induced mammary tumor model, showed that removal of PGR function results in a significant reduction in susceptibility to 7,12-dimethylbenz(a)anthracene-induced mammary tumors (13) . Studies of transgenic mice that carried either an additional -A or -B form reported that mammary development was abnormal and characterized by excessive lateral ductal branching and inappropriate alveolar growth (14) . Considering the epidemiological and biological evidence described above for the role of progesterone in breast cancer causation, we hypothesized that variation in the PGR gene may predispose women to breast cancer. Several polymorphisms have been identified in PGR, they include S344T, G393G, V660L, H770H, and the PROGINS allele (15) . In this study, we evaluated the promoter polymorphism, +331 G/A, for two reasons: its association with endometrial cancer, a hormonally related disease, and because it has established function. We do not plan to evaluate the other PGR polymorphisms because they are not known to be functional, and we did not observe an association with endometrial cancer (15) .


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Study Population.
The Nurses’ Health Study was initiated in 1976, when 121,700 United States registered nurses between the ages of 30 and 55 returned an initial questionnaire reporting medical histories and baseline health-related exposures. Between 1989 and 1990, blood samples were collected from 32,826 women. Incident breast cancers were identified by self-report and confirmed by medical record review. Eligible cases in this study consisted of women diagnosed with pathologically confirmed incident breast cancer after giving a blood specimen up to June 1, 1994. Controls were matched to cases on year of birth, menopausal status, postmenopausal hormone use, and time of day, month, and fasting status at blood draw; menopause was defined as described previously (16) . The nested case-control study consists of 990 incident breast cancer cases and 1,364 matched controls. The protocol was approved by the Committee on Human Subjects, Brigham and Women’s Hospital. Detailed information on exposure data has been described previously (16 , 17) .

Laboratory.
Genotyping assays were performed by RFLP as described previously (15) , and the 5' nuclease assay (TaqMan) was performed with the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). TaqMan primers, probes, and conditions for genotyping assays are available on request from authors. Genotyping was performed by laboratory personnel blinded to case-control status, and blinded quality control samples were inserted to validate genotyping procedures. Concordance for the blinded samples was 100%.

Statistical Analysis.
Student’s t test and the {chi}2 test were used to evaluate differences in breast cancer risk factors between cases and controls. ORs and 95% CIs were calculated by using conditional and unconditional logistic regression. In addition to the matching variables, we adjusted for breast cancer risk factors: BMI (kg/m2) at age 18 years, weight gain since age 18, age at menarche, parity/age at first birth, duration of postmenopausal hormone use, first-degree family history of breast cancer, and history of benign breast disease. We also adjusted for age at menopause in analyses limited to postmenopausal women. Indicator variables for all genotypes were created by using the wild-type hypothesized low-risk genotype as the reference category in the regression models. Because of the low prevalence of homozygote variants (AA), we combined heterozygotes (AG) and homozygote variants (AA) in the logistic regression analysis. Interactions between genotypes and breast cancer risk factors were evaluated by including appropriate interaction terms in unconditional logistic regression models. The likelihood ratio test was used to assess the statistical significance of these interactions. We used SAS version 8.0 (SAS Institute, Cary, NC) for all analyses. We tested Hardy-Weinberg agreement by using a {chi}2 test.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Our study included a total of 990 incident breast cancer cases and 1,364 controls. Eight hundred twenty cases and 1,167 controls were postmenopausal, and 102 cases and 110 controls were premenopausal; menopausal status was uncertain in 68 cases and 87 controls. The mean age of cases at blood draw was 57.2 years; for controls, it was 57.9 years. Cases and controls had similar mean BMI at blood draw (25.4 versus 25.5 kg/m2) and weight gain since age 18 years (11.7 versus 11.5 kg). Compared with controls, cases had similar ages at menarche (12.5 versus 12.6 years), first birth (23.0 versus 22.9 years), and menopause (48.2 versus 48.0 years). The proportion of women with a first-degree family history of breast cancer was significantly higher among the cases (21.1% versus 14.5%; P = 0.001). Cases were also more likely to have a history of benign breast disease (64.8% versus 49.3%; P < 0.001) and a longer duration of postmenopausal hormone use (30.3% versus 22.6% current users for 5 or more years; P = < 0.001).

The prevalence of the AA carriers was similar to a previous report for Caucasian women (15) , 13% for the cases and 10% for the controls. The genotype distribution of the +331 G/A polymorphism among the cases and controls was in Hardy-Weinberg equilibrium (P = 0.11). We observed a statistically significant increased risk of breast cancer among carriers of the +331 G/A polymorphism; compared with the +331 G/G wild-type genotype, the adjusted OR for women with +331 G/A and +331 A/A was 1.33 (95% CI, 1.01–1.74; Table 1Citation ). After stratifying by menopausal status, the association was similar among postmenopausal women (adjusted OR, 1.41; 95% CI, 1.06–1.87) but not among premenopausal women (Table 1)Citation . Too few homozygote variants were available to analyze the heterozygous and homozygous women separately. The +331 G/A polymorphism has been shown to modify the association between BMI and endometrial cancer risk (15) , a hormonally related cancer, and obesity is directly related to breast cancer only among postmenopausal women (18) . Huang et al. observed a modest nonsignificant association between postmenopausal obese women (BMI >= 30 kg/m2) and breast cancer risk. Compared with lean women (<25 kg/m2), the OR for postmenopausal women with a BMI of 25 to <30 and >=30 kg/m2 was 1.06 (95% CI, 0.82–1.37) and 1.24 (95% CI, 0.78–1.95), respectively (18) . We sought to determine whether the +331 G/A genotype modified the effect of BMI on breast cancer risk among postmenopausal women. We observed a statistically significant association between postmenopausal obese women (BMI >=30 kg/m2) who carried at least one A allele and breast cancer risk (Table 2)Citation . Compared with wild-type (+331 G/G) lean women (<25 kg/m2), the OR for postmenopausal women carriers with a BMI of 25 to <30 kg/m2 and >=30 kg/m2 was 1.98 (95% CI, 1.16–3.39) and 2.30 (95% CI, 1.02–5.21), respectively (Table 2)Citation . The test for interaction, however, was not statistically significant (P for interaction, likelihood ratio test = 0.10). We observed no significant interactions with first-degree family history of breast cancer, a history of benign breast disease, or hormone replacement therapy use.


View this table:
[in this window]
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  		Table 1 Association between PGR polymorphism and breast cancer risk

 

View this table:
[in this window]
[in a new window]
  		Table 2 PR polymorphisms and BMI for postmenopausal women only: frequencies and ORs for breast cancer risk

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
PGR polymorphisms, most notably the PROGINS allele, have been studied in relation to breast and ovarian cancer (19, 20, 21) . Wang-Gohrke et al. (20) found an inverse association between breast cancer risk in women younger than 50 years and carriers of the PROGINS allele. In contrast, Spurdle et al. (21) found no association between Val660Leu, a polymorphism that is in complete linkage disequilibrium with PROGINS, and breast cancer risk in women of comparable age. To our knowledge, this is the first population-based study to examine the functional PGR polymorphism, +331 G/A, in relation to breast cancer risk. We observed a modestly significant increase in breast cancer risk among women with AG or AA genotypes (adjusted OR, 1.33; 95% CI, 1.01–1.74) compared with women with GG genotypes, and the effect was similar in postmenopausal women (adjusted OR, 1.41; 95% CI, 1.06–1.87). We have shown previously that a consequence of this polymorphism is an increase in the expression of the hPR-B isoform (15) . Biological studies have convincingly shown that the two PGR isoforms, hPR-A and hPR-B, are functionally distinct (10 , 11 , 22 , 23) . In contrast to hPR-A, hPR-B is a potent transcriptional activator, and hPR-B alone can promote cell growth by interacting with the estrogen receptor to stimulate the Src/p21ras/extracellular signal-regulated kinase pathway (24) . Moreover, recent microarray analysis confirmed that each PGR isoform, expressed in a breast cancer cell line, has a unique set of target genes, with little overlap (12) . Genes selectively up-regulated by hPR-B that predispose to mammary cell survival and proliferation include IAP homologue C and cyclin D3, as well as antiapoptotic protein BcL-XL (12) . Taken together, these data suggest that increased production of hPR-B by the +331 G/A polymorphism may predispose to cancer development through increased hPR-B-dependent stimulation of mammary cell growth.


   ACKNOWLEDGMENTS
 
We thank the participants of the Nurses’ Health Study for continuing exceptional cooperation. We thank Rong Chen, Pamela Lescault, and Hardeep Ranu for technical assistance.


   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.

1 This work was supported by NIH Grants CA82838 (to I. D.), CA87969, and CA49449 and American Cancer Society Grant RSG-00-061-04 CCE. Back

2 To whom requests for reprints should be addressed, at Channing Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-2094; Fax: (617) 525-2008; E-mail: devivo{at}channing.harvard.edu Back

3 The abbreviations used are: PRKO, progesterone receptor knockout; PGR, progesterone receptor; PR-A and PR-B, progesterone receptor isoform A and B, respectively; hPR, human PR; OR, odds ratio; CI, confidence interval; BMI, body mass index. Back

Received 5/ 9/03. Revised 7/ 1/03. Accepted 7/ 9/03.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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 Cancer Epidemiol. Biomarkers Prev.Home page
H. S. Feigelson, C. Rodriguez, E. J. Jacobs, W. R. Diver, M. J. Thun, and E. E. Calle
No Association between the Progesterone Receptor Gene +331G/A Polymorphism and Breast Cancer
Cancer Epidemiol. Biomarkers Prev., June 1, 2004; 13(6): 1084 - 1085.
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J. Wu, J. Richer, K. B. Horwitz, and S. M. Hyder
Progestin-Dependent Induction of Vascular Endothelial Growth Factor in Human Breast Cancer Cells: Preferential Regulation by Progesterone Receptor B
Cancer Res., March 15, 2004; 64(6): 2238 - 2244.
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V. W. Setiawan, S. E. Hankinson, G. A. Colditz, D. J. Hunter, and I. De Vivo
HSD17B1 Gene Polymorphisms and Risk of Endometrial and Breast Cancer
Cancer Epidemiol. Biomarkers Prev., February 1, 2004; 13(2): 213 - 219.
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