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

A Functional Polymorphism in the Progesterone Receptor Gene Is Associated with an Increase in Breast Cancer Risk1,Immaculata De Vivo,Susan E. Hankinso

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A Functional Polymorphism in the Progesterone Receptor Gene Is Associated with an Increase in Breast Cancer Risk1   (Citations: 19)
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Biological and epidemiological data suggest that progesterone has an important role in mammary tumorigenesis. Because the effects of proges- terone 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 sig- nificant 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 inter- action between genotype and body mass index (BMI) among postmeno- pausal 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 mam- mary cell growth.
Published in 2008.
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    • ...We did not observe a significant main effect of PGR genotypes with breast cancer, which is consistent with some reports (23, 25), but not others (22, 24)...

    T. R. Rebbeck, et al. Pharmacogenetic Modulation of Combined Hormone Replacement Therapy by ...

    • ...A second variant in PGR, the putatively functional promoter SNP 331G/A, was associated with an increased risk of breast cancer in one study (38) but not in another (39)...
    • ...Although the putative functional SNP 331G/A fell in an interblock region, it was genotyped in the case patients and control subjects because it had previously been reported to be associated with risk of breast cancer (38)...
    • ...SNP 331G/A and risk of breast cancer when considering all case patients (Supplementary Table 2, available at: http:// jncicancerspectrum.oupjournals.org/jnci/content/vol97/issue1) or after stratifying by body mass index (data not shown), as was found by De Vivo et al. (38)...
    • ...The putatively functional 331G/A SNP, which was previously found by De Vivo et al. (38) but not by Feigelson et al. (39) to be associated with breast cancer, was not associated with breast cancer in our study (Supplementary Table 2, available at: http://jncicancerspectrum.oupjournals.org/jnci/content/vol97/ issue1)...

    Celeste Leigh Pearce, et al. Clarifying the PROGINS Allele Association in Ovarian and Breast Cancer...

    • ...A virtually identical pattern of increased risk with the A allele among all women and particularly postmenopausal ones has been observed for breast cancer in a nested case-control sample from the Nurses’ Health Study (7)...

    Harvey A. Risch, et al. PGR +331 A/G and Increased Risk of Epithelial Ovarian Cancer

    • ...Previously, we also reported a modest association of the hPR +331G/A variant with breast cancer risk in the Nurse’s Health Study cohort (22)...
    • ...A modest association between the +331A alleleand theriskof breastcancerhasbeen reported (22).Toachieve greater statistical power, we genotyped all additional 308 cases and matched controls to confirm this finding...
    • ...The prevalence of the variant carriers was similar to a previous report for Caucasian women (22), 13% for the cases and 10% for the controls...
    • ...In addition to endometrial cancer (21), we found a modest association between the +331G/A variant and breast cancer risk (22)...

    Gordon S. Huggins, et al. GATA5 Activation of the Progesterone Receptor Gene Promoter in Breast ...

    • ...Alternatively, increased PRB expression has been linked to cell proliferation in patients with breast cancer (27), whereas in mice,...
    • ...We propose that this effect is a direct consequence of high PRB expression and is consistent with the observations that PRB is essential for mammary development, proliferation, and differentiation, whereas PRA is not (20) and that carriers of the PR +331 A allele, which leads to increased expression of PRB, are at increased risk of breast cancer (27)...

    Eileen M. McGowan, et al. Progestins Reinitiate Cell Cycle Progression in Antiestrogen Arrested ...

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