This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, S. L. Articles by Gao, Y.-T. Search for Related Content PubMed PubMed Citation Articles by Zheng, S. L. Articles by Gao, Y.-T.

Joint Effect of Estrogen Receptor ß Sequence Variants and Endogenous Estrogen Exposure on Breast Cancer Risk in Chinese Women

¹ Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina;
² Department of Medicine and Vanderbilt-Ingram Cancer Center, School of Medicine, Vanderbilt University, Nashville, Tennessee;
³ Department of Epidemiology and Public Health and Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut;
⁴ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

	ABSTRACT

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Long-term estrogen exposure and family history of breast cancer are the two factors that are most consistently found to be associated with breast cancer risk. Sequence variants in genes involved in estrogen synthesis, metabolism, and signal transduction may account, in part, for this observation. Using data and DNA samples from the Shanghai Breast Cancer Study, we tested the hypothesis that sequence variants of the estrogen receptor ß gene (ESR2) may be associated with increased risk for breast cancer, particularly among women who have a high level and long-term endogenous estrogen exposure. Direct sequencing of the ESR2 gene among 30 Chinese women revealed eight sequence variants. Association analysis of six common sequence variants in 1134 cases and 1235 controls provided evidence for positive associations between breast cancer risk and two single nucleotide polymorphisms (SNPs), [C(14206)T and C(33390)G], among postmenopausal women. Evidence of a stronger association was found for SNP [C(33390)G] among women with a long duration (34 years) of menstruation (odds ratio, 2.37; 95% confidence interval, 1.18–4.77). A potential synergistic effect between SNP [C(33390)G] and several steroid sex hormones was observed, and a 3–4-fold elevated risk of breast cancer was found among women with a CG or GG genotype in SNP [C(33390)G] combined with a high level of steroid sex hormone or a low level of sex hormone binding globulin. Our results are consistent with the hypothesis of a joint effect of estrogen receptor ß sequence variants and endogenous estrogen exposure on breast cancer risk.

	Introduction

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Breast cancer is the leading cancer among women in most parts of the world, including Shanghai, the largest industrialized city in China. The annual incidence rate for breast cancer was 27.5 per 100,000 in Shanghai during 1993–94, approximately one-third of the rate for their Caucasian counterparts in the United States (1) . The etiology for this common malignancy remains largely unknown. Of the many risk factors identified for breast cancer, long-term estrogen exposure and family history of breast cancer, are the two factors most consistently reported from previous studies, including our studies in Shanghai (2) . In our recent study from Shanghai, we have shown that women with breast cancer had substantially higher blood estrogen levels than controls, and a >2-fold elevated risk of breast cancer was found among postmenopausal women in the upper tertile of blood testosterone or estrone, compared with those in the low tertile of these steroid sex hormones (3) .

Similar to other complex diseases, it is likely that a combination of genetic susceptibility and exposure to endogenous and exogenous factors increase the risk to breast cancer. Mutations in high penetrance cancer susceptibility genes, such as the BRCA1 and BRCA2 genes, confer a substantially elevated risk; however, they only account for <10% of breast cancer cases in the general population due to their low mutation frequencies. Other genes, particularly those involved in estrogen synthesis, metabolism, and signal transduction, may also be important in the etiology of breast cancer. Estrogen signaling is largely mediated by ERs⁵ and ß (ESR1 and ESR2); both are members of the nuclear receptor superfamily of ligand-inducible transcription factors. Although the ESR1 and ESR2 genes have a high sequence similarity in their DNA- and ligand-binding domains, they have distinct transcriptional activating function-1 domains and are believed to possess different transcriptional activation properties (4) . ESR1 and ESR2 have distinct tissue and cell expression patterns. In normal breast tissue, ESR2 is constitutively expressed and is the predominant ER in most cells. Various ESR2 splicing variants have been found, and some of the splicing variants have been shown to encode proteins in both normal and cancerous tissues (5 , 6) . In breast cancer, the presence of ESRs is correlated with higher responsiveness to hormone therapy and better prognosis. Thus far, the majority of epidemiological association studies have focused on evaluating the association between genetic polymorphisms in ESR1 and breast cancer risk. However, the results for several commonly examined ESR1 genetic polymorphisms have been mixed (7) . We reported recently some results from a large population-based case-control study among Chinese women in Shanghai, showing that breast cancer risk was associated with the PvuII polymorphism in intron 1 (8) and a GT dinucleotide repeat polymorphism in the promoter region of the ESR1 gene (9) . In the current study, we evaluated the hypothesis that certain sequence variants of the ER ß gene (ESR2) are associated with an increased risk for breast cancer, particularly among women who have a high level and long-term of estrogen exposure. This study includes the following components: (a) direct sequencing of the exons, exon-intron junctions, and the promoter region to identify sequence variants of the ESR2 gene among 30 Chinese women; (b) genotyping seven relatively common sequence variants among all of the cases and controls whose DNA samples were available at the time of this study; and (c) assessment of the association of ESR2 sequence variants and their interaction with estrogen exposure on breast cancer risk.

	Materials and Methods

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
Study Population.
Included in the study were subjects recruited during 1996–1998 in the Shanghai Breast Cancer study, a population-based case-control study of Chinese women in Shanghai. A detailed description of the study was provided elsewhere (2 , 10) . Briefly, 1459 incident breast cancer patients 25–64 years of age were enrolled in the study, along with 1556 healthy control women who had a similar age distribution to the cases based on frequency match. During the study, newly diagnosed breast cancer patients were identified through a rapid case-ascertainment system, supplemented by the population-based Shanghai Cancer registry. The cases enrolled in our study represented 91% of the newly diagnosed breast cancer patients identified for our study during the study period. The controls were randomly selected from the general population in Shanghai, using resident registration information provided by the Shanghai Resident Registry, which registers all of the permanent residents in urban Shanghai. Before random selection, we first determined the number of controls needed in each age group, at 5-year intervals, based on the number of cases in the corresponding age group reported to the Shanghai Cancer Registry in recent years. Once the numbers were determined, potential controls were randomly selected using their resident registration number. After the study eligibility of the identified potential control was confirmed, and an in-person interview was scheduled and conducted by a trained interviewer. Of those who were eligible for study, 90% completed an in-person interview.

The in-person interview was done with the use of a structured questionnaire, which elicited information on demographic features, menstrual and reproductive history, use of sex steroid hormones, medical history, physical activity, alcohol and tobacco use, dietary habits, and family history of cancer. Of the 1459 cases and 1556 controls who completed the in-person interview, morning fasting blood samples were collected from 1193 cases (82%) and 1310 controls (84%). The blood samples were processed to separate plasma within 6 h of collection, and the plasma specimens were immediately stored at -70°C. DNA samples of 2369 subjects were available at the time of the study.

We measured sex steroid hormones in a subset of cases and controls. Cases included in this substudy were those whose blood samples were collected before any cancer treatment. All of the postmenopausal cases and controls and 171 premenopausal case-control pairs were included in the study. For premenopausal women, the cases and controls were matched individually on (+5 years) and their menstrual cycle, which was either within the first 10 days of the menstrual cycle, matching mainly on follicular phase, or within 3 days after the first 10 days, matching either on follicular phase or luteal phase. To control for potential between assay variability, we adjusted the batch of hormone assay in data analysis.

Genotyping Methods.
The PCR products of 9 exons, exon-intron junctions, the promoter region, and 3' UTR of ESR2 were sequenced directly in 15 early onset breast cancer cases and 15 controls. The primers for PCR are available.⁶ All of the PCR reactions were performed in a 10-µl volume consisting of 30 ng genomic DNA, 0.2 mM of each primer, 0.2 mM of each dNTP, 1.5 mM MgCl_2, 20 mM Tris-HCl, 50 mM KCl, and 0.5 unit of Taq polymerase (Life Technologies, Inc.). PCR cycling conditions were as follows: 94°C for 4 min; followed by 30 cycles of 94°C for 30 s, specified annealing temperature for 30 s, and 72°C for 30 s; with a final extension of 72°C for 6 min. All of the PCR products were purified using the QuickStep PCR purification kit (Edge BioSystems, Gaithersburg, MD) to remove dNTPs and excess primers. All of the sequencing reactions were performed using dye-terminator chemistry (BigDye; ABI, Foster City, CA) and then precipitated using 63 ± 5% ethanol. Samples were loaded onto an ABI 3700 DNA Analyzer after adding 8 µl of formamide. SNPs were identified using Sequencher software version 4.0.5 (Gene Codes Corporation).

SNP genotyping was performed at the Center for Human Genomics, Wake Forest University School of Medicine. All of the investigators at Wake Forest University were blinded to the case-control status. To ensure the quality of genotyping, each 96-well DNA plate was embedded with two duplicates of our study subjects, two duplicates of Centre d’Etude du Polymorphisme Humain controls (1347–02), and one water blank. All of the duplicates were later determined to be identical for all seven of the SNPs, and no genotype was observed for any of the blanks. SNPs were genotyped using the MassARRAY system (SEQUENOM, Inc., San Diego, CA). PCR reactions were performed in a total volume of 5 µl with 10 ng of genomic DNA, 2.5 mM of MgCl₂, 0.1 unit of HotStarTaq polymerase (Qiagen Inc., Valencia, CA), 200 µM of dNTP, and 200 nM of primers. The PCR reactions started at 95° for 15 min, followed by 45 cycles of 95° for 20 s, 50° for 30 s, and 72° for 1 min, with a final extension of 72° for 3 min. The homogenous Mass Extend (hME) reactions were performed in a total volume of 9 µl with 50 µM each deoxynucleotide triphosphate/dideoxynucleotide triphosphate (d/ddNTP), 0.063 µ/µl of Thermo Sequenase (both from SEQUENOM, Inc.), and 600 nM of extension primers. The cycling conditions were 94° for 2 min, followed by 55 cycles of 94° for 5 s, 52° for 5 s, and 72° for 5 s. After cleaning up the hME reaction products with the SpectroCLEAN, the products were transferred to a SpectroCHIP using SpectroPOINT, and then scanned through SpectroREADER. Genotyping was done using SpectroTYPER.

Measurement of Steroid Hormones and Sex Hormone-Binding Globulin (SHBG).
A detailed description of the measurement of steroid hormones and SHBG was provided elsewhere (3) . Plasma concentrations of testosterone, estradiol, estrone, estrone sulfate, DHEA-S, and progesterone were measured directly without extraction. Measurement of steroids and SHBG in our study was performed in a reference laboratory, at DSL (Webster, TX). Commercial RIAs from DSL were used for the measurement of steroids; an immunoradiometric assay from DSL was used for SHBG. Technicians who performed the tests did not know the source of the specimens.

Statistical Methods.
Hardy-Weinberg Equilibrium tests for each sequence variant and pair-wise LD tests among all of the sequence variants were performed using the Fisher probability test statistic, as described by Weir (11) . For each test, 10,000 permutations were performed, and the test statistic of each replicate was calculated. Empirical Ps for each test were estimated as the proportion of replicates that were as probable as or less probable than the observed data, as implemented in the software package Genetic Data Analysis. Various estimates of pair-wise LD such as Lewontin’s D’ and the correlation coefficient were calculated using the computer software SAS/Genetics.

Tests for association between sequence variants and breast cancer were performed by comparing the allele frequencies between cases and controls in a ² test with 1 degree of freedom using the computer software SAS/Genetics. Risk genotypes were arbitrarily defined based on the alleles that were more common in cases than in controls and assuming a dominant model; i.e., homozygous and heterozygous variant alleles as risk genotypes, and homozygous nonrisk allele as a reference genotype. The choice of dominant models was primarily because of the few homozygous risk allele carriers in this population. Estimates of RR were calculated and adjusted for potential confounders.

Association between the haplotypes of the six SNPs and breast cancer risk was also performed using a score test developed by Schaid et al. (12) , as implemented in the computer program HAPLO.SCORE.⁷

For each steroid hormone, subjects were classified into low or high levels based on the pre- or postmenopausal specific median levels. Years of menstruation were calculated for postmenopausal women (age at menopause - age at menarche), and premenopausal women (age at diagnosis - age at menarche for cases, or age at interview - age at menarche for controls).

	Results

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
The characteristics of cases and controls in this study are presented in Table 1 . Risk factors identified from this study were consistent with those reported elsewhere (13) . Sequence analysis in a subset of 30 subjects revealed eight sequence variants (Table 2) . Among these, three are in the promoter region, two are in the coding regions (both are synonymous changes), two are in the 3'UTR, and one is in intron 5.

	Discussion

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 
We hypothesize that sequence variants of the ER ß gene (ESR2) are associated with an increased risk for breast cancer, particularly among women who have a high-level and long-term estrogen exposure. This hypothesis was primarily based on consistent epidemiological evidence and strong biological support for the critical roles of steroid hormones, via activating ERs in the regulation of mammary cell growth and differentiation. Numerous epidemiological studies consistently suggest factors, such as early age at menarche and late age at menopause, that increase the number of menstrual cycles (and therefore lengthen the exposure to estrogens) elevating breast cancer risk (14) . Studies from basic biology have shown that estrogens are strong mitogens for mammary cells, and numerous animal studies have demonstrated that estrogens can induce and promote breast cancer, whereas the removal of ovaries or administration of antiestrogens such as tamoxifen can oppose the carcinogenesis process (14 , 15) . Estrogen action is mediated primarily through binding to ERs (ESRs), which then act as transcriptional factors by binding to specific ER elements of target genes (16 , 17) , interact with other transcriptional factors such as SP1, AP1, or nuclear factor B in the absence of DNA binding (18, 19, 20, 21) , or crosstalk with proteins in other signaling pathways such as raf-mitogen-activated protein kinase signaling and phosphatidylinositol 3'-kinase/Akt signaling pathways via nongenomic effects (4 , 22) .

Most of the previous studies have focused on ER (ESR1), and several epidemiological studies have shown that genetic polymorphisms in the ESR1 gene may be associated with breast cancer risk (9 , 10 , 23) . The importance of ESR2 in breast cancer has not been recognized until very recently (24) . ESR2 and ESR1 have distinct cellular distributions, regulate separate sets of genes, and oppose each other’s actions when regulating some genes. ESR2 is widely expressed in both normal and malignant breast, and there are proliferating cells in the breast that express ESR2. Considering the fact that only a subset of women who have a high level or long-term estrogen exposure develop breast cancer, it is possible that the risk of breast cancer may be modified by polymorphisms in genes, such as ESR2, that are involved in the regulation of estrogen effect in breast tissues. The results of this study appear to be consistent with this hypothesis.

However, caution should be taken when interpreting our findings. In particular, type I errors are a concern in association studies of genetic polymorphisms, given the fact that multiple comparisons are often made. It is difficult, however, to adjust the Ps for multiple comparisons in this study, because these sequence variants are not independent due to strong LD. The hormone levels are not independent either, with significant interclass correlation coefficients. In addition, because the functional relevance of the polymorphisms evaluated is unknown, additional epidemiological studies and functional studies are needed.

Our results are also susceptible to multiple sources of measurement variation associated with steroid hormones. However, we have paid particular attention to minimize such random variation by using an individual matched study design that enhances the comparability between cases and controls, as well as by minimizing the variability of laboratory testing from batch to batch (between-assay variation).

At present, the mechanism by which the SNP C(33390)G interacts with hormones and affects breast cancer risk is unknown. The observed association may be due to a causal effect of the SNP or through other as yet unknown flanking sequence variants in LD with this SNP. Although C(33390)G is a silent synonymous change, results from multiple studies have shown that synonymous changes may inactivate genes by inducing the splicing machinery to skip the exons (25, 26, 27, 28) . In fact, the SNP C(33390)G is located in an exonic splicing enhancer motif (in the binding site for splice factor SC35), and, thus, may affect the accuracy and efficiency of ESR2 pre-mRNA splicing. The C allele of C(33390)G was preferentially found in the SC35 enhancer element at this particular position (has above background frequency in SC35 consensus sequence), whereas the G allele had below background frequency and may have an adverse effect on the splicing efficiency of exon 7. In addition, we observed an association between G allele carriers of the SNP and self-reported fibroadenoma risk in our study (10.5% in 172 cases versus 5.5% in 2140 controls; RR, 2.0; 95% CI, 1.19–3.38; data not shown), providing additional support for a potential functional impact of this variant.

It is worth noting that the joint effect of higher estrogen levels and ESR2 sequence variants was consistently observed for multiple estrogens and estrogen-related steroids, including DHEA-S. One of the major sources of steroid hormones in women is the synthesis in intracrine tissues from the inactive precursors DHEA and DHEA-S of adrenal origin; this intracrine synthesis is especially important after menopause. The importance of steroid hormones from an intracrine source is illustrated by several clinical trials that describe the benefits of aromatase (which converts androgens to estrones) inhibitors in the treatment of hormone-responsive metastasis (ER+) as well as primary breast cancers in women (29, 30, 31) . Higher circulating DHEA as well as its sulfate conjugate (DHEA-S) provides the peripheral target tissues more estrogen precursor and may lead to higher local estrogen levels. Higher estrogen levels, when conjugated with ESR that has increased activity, can additionally increase the risk of breast cancer. Again, caution should be exercised when interpreting the interaction effect, especially given the small sample size for this particular part of the study.

Our results, if confirmed, may have significant implications in the prevention of breast cancer. Women with the "high-risk" ESR2 sequence variants could reduce their risk for breast cancer by reducing their estrogen levels.

	ACKNOWLEDGMENTS

 
We thank all of the study subjects who participated in this study.

	FOOTNOTES

 
Grant support:USPHS Grants R01CA64277 and R01CA90899 from the National Cancer Institute (W. Z.); partially supported by a grant from the Department of Defense to (J. X.).

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.

Requests for reprints:Wei Zheng, Center for Health Services Research, Vanderbilt University Medical Center, Medical center East, Suite 6000, Nashville, TN 37232-8300. E-mail: wei.zheng{at}vanderbilt.edu or Jianfeng Xu, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: jxu{at}wfubmc.edu

⁵ The abbreviations used are: ER, estrogen receptor; CI, confidence interval; UTR, untranslated region; dNTP, deoxynucleotide triphosphate; DHEA, dehydroepiandrosterone; S, sulfate; DSL, Diagnosed Systems Laboratory Inc.; LD, linkage disequilibrium; RR, relative risk; BMI, body mass index; SNP, single nucleotide polymorphisms.

⁶ Internet address: http://www.wfubmc.edu/genomics.

⁷ Internet address: http://www.mayo.edu/statgen for the S-PLUS programming language or http://www.wfubmc.edu/genomics for the R programming language.

Received 7/ 8/03. Revised 8/21/03. Accepted 8/26/03.

	REFERENCES

Top ABSTRACT Introduction Materials and Methods Results Discussion REFERENCES

 

1. Jin F., Devesa S. S., Chow W. H., Zheng W., Ji B. T., Fraumeni J. F., Jr., Gao Y. T. Cancer incidence trends in urban shanghai, 1972–1994: an update. Int. J. Cancer, 83: 435-440, 1999.[Medline]
2. Gao Y. T., Shu X. O., Dai Q., Potter J. D., Brinton L. A., Wen W., Sellers T. A., Kushi L. H., Ruan Z., Bostick R. M., Jin F., Zheng W. Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study. Int. J. Cancer, 87: 295-300, 2000.[Medline]
3. Yu H., Shu X. O., Shi R., Dai Q., Jin F., Gao Y. T., Li B. D., Zheng W. Plasma sex steroid hormones and breast cancer risk in Chinese women. Int. J. Cancer, 105: 92-97, 2003.[Medline]
4. Sanchez R., Nguyen D., Rocha W., White J. H., Mader S. Diversity in the mechanisms of gene regulation by estrogen receptors. Bioessays, 24: 244-254, 2002.[Medline]
5. Speirs V., Adams I. P., Walton D. S., Atkin S. L. Identification of wild-type and exon 5 deletion variants of estrogen receptor ß in normal human mammary gland. J. Clin. Endocr. Metab., 85: 1601-1605, 2000.[Abstract/Free Full Text]
6. Poola I., Abraham J., Liu A. Estrogen receptor ß splice variant mRNAs are differentially altered during breast carcinogenesis. J. Steroid. Biochem. Mol. Biol., 82: 169-179, 2002.[Medline]
7. de Jong M. M., Nolte I. M., te Meerman G. J., van der Graaf W. T., Oosterwijk J. C., Kleibeuker J. H., Schaapveld M., de Vries E. G. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J. Med. Genet., 39: 225-242, 2002.[Abstract/Free Full Text]
8. Zheng W., Xie D. W., Jin F., Cheng J. R., Dai Q., Wen W. Q., Shu X. O., Gao Y. T. Genetic polymorphism of cytochrome P450–1B1 and risk of breast cancer. Cancer Epidemiol. Biomark. Prev., 9: 147-150, 2000.[Abstract/Free Full Text]
9. Cai Q., Shu X-O., Dai Q., Wen W., Cheng J-R, Gao Y-T., Zheng W. Genetic polymorphisms of the estrogen receptor- gene and risk of breast cancer: Results from the Shanghai Breast Cancer Study. Cancer Epidemiol. Biomark. Prev., : in press 2003.
10. Cai Q. Y., Gao Y. T., Smith J., Wen W., Shu X. O., Jin F., Zheng W. A GT dinucleotide repeat polymorphism upstream of the estrogen receptor- gene in relation to breast cancer risk. Cancer Res., : in press 2003.
11. Weir B. S. . Genetic Data Analysis II: Methods for Discrete Population Genetic Data, Sinauer Association, Inc. Publishers Sunderland, MA 1996.
12. Schaid D. J., Rowland C. M., Tines D. E., Jacobson R. M., Poland G. A. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J.Hum. Genet., 70: 425-434, 2002.
13. Nathanson K. L., Weber B. L. Breast cancer King R. A. Rotter J. I. Motulsky A. G. eds. . The Genetic Basis of Common Diseases, 670-699, Oxford University Press, Inc. New York 2002.
14. Hulka B. S., Moorman P. G. Breast cancer: hormones and other risk factors. Maturitas, 38: 103-113, 2001.[Medline]
15. Vignon F., Bouton M. M., Rochefort H. Antiestrogens inhibit the mitogenic effect of growth factors on breast cancer cells in the total absence of estrogens. Biochem. Biophys. Res. Commun., 146: 1502-1508, 1987.[Medline]
16. Tsai M. J., O’Malley B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem., 63: 451-486, 1994.[Medline]
17. Dickson R. B., Stancel G. M. Estrogen receptor-mediated processes in normal and cancer cells. J. Natl. Cancer Inst. Monogr., : 135-145, 2000.
18. Batistuzzo d. M., Sr., Krey G., Hihi A. K., Wahli W. Functional interactions between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 io promoter. J. Biol. Chem., 272: 18250-18260, 1997.[Abstract/Free Full Text]
19. Galien R., Evans H. F., Garcia T. Involvement of CCAAT/enhancer-binding protein and nuclear factor- B binding sites in interleukin-6 promoter inhibition by estrogens. Mol. Endocrinol., 10: 713-722, 1996.[Abstract/Free Full Text]
20. Paech K., Webb P., Kuiper G. G., Nilsson S., Gustafsson J., Kushner P. J., Scanlan T. S. Differential ligand activation of estrogen receptors ER and ERß at AP1 sites. Science (Wash. DC), 277: 1508-1510, 1997.[Abstract/Free Full Text]
21. Porter W., Saville B., Hoivik D., Safe S. Functional synergy between the transcription factor Sp1 and the estrogen receptor. Mol. Endocrinol., 11: 1569-1580, 1997.[Abstract/Free Full Text]
22. Lee A. V., Cui X., Oesterreich S. Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin. Cancer Res., 7: 4429s-4435s, 2001.
23. Kang H. J., Kim S. W., Kim H. J., Ahn S. J., Bae J. Y., Park S. K., Kang D., Hirvonen A., Choe K. J., Noh D. Y. Polymorphisms in the estrogen receptor- gene and breast cancer risk. Cancer Lett., 178: 175-180, 2002.[Medline]
24. Palmieri C., Cheng G. J., Saji S., Zelada-Hedman M., Warri A., Weihua Z., Van Noorden S., Wahlstrom T., Coombes R. C., Warner M., Gustafsson J. A. Estrogen receptor ß in breast cancer. Endocr. Relat. Cancer, 9: 1-13, 2002.[Abstract]
25. Cartegni L., Chew S. L., Krainer A. R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat. Rev. Genet., 3: 285-298, 2002.[Medline]
26. Caputi M., Kendzior R. J., Jr., Beemon K. L. A nonsense mutation in the fibrillin-1 gene of a Marfan syndrome patient induces NMD and disrupts an exonic splicing enhancer. Genes Dev., 16: 1754-1759, 2002.[Abstract/Free Full Text]
27. Cartegni L., Krainer A. R. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet., 30: 377-384, 2002.[Medline]
28. Fackenthal J. D., Cartegni L., Krainer A. R., Olopade O. I. BRCA2 T2722R is a deleterious allele that causes exon skipping. Am. J. Hum. Genet., 71: 625-631, 2002.[Medline]
29. Lake D. E., Hudis C. Aromatase inhibitors in breast cancer: an update. Cancer Control, 9: 490-498, 2002.[Medline]
30. Coleman R. E. Current and future status of adjuvant therapy for breast cancer. Cancer (Phila.), 97: 880-886, 2003.
31. Cuzick J., Powles T., Veronesi U., Forbes J., Edwards R., Ashley S., Boyle P. Overview of the main outcomes in breast-cancer prevention trials. Lancet, 361: 296-300, 2003.[Medline]

This article has been cited by other articles:

				C. Thellenberg-Karlsson, S. Lindstrom, B. Malmer, F. Wiklund, K. Augustsson-Balter, H.-O. Adami, P. Stattin, M. Nilsson, K. Dahlman-Wright, J.-A. Gustafsson, et al. Estrogen Receptor {beta} Polymorphism Is Associated with Prostate Cancer Risk Clin. Cancer Res., March 15, 2006; 12(6): 1936 - 1941. [Abstract] [Full Text] [PDF]

				Y. Shen, D.-K. Li, J. Wu, Z. Zhang, and E. Gao Joint Effects of the CYP1A1 MspI, ER{alpha} PvuII, and ER{alpha} XbaI Polymorphisms on the Risk of Breast Cancer: Results from a Population-Based Case-Control Study in Shanghai, China. Cancer Epidemiol. Biomarkers Prev., February 1, 2006; 15(2): 342 - 347. [Abstract] [Full Text] [PDF]

				P. Nancy and S. Berrih-Aknin Differential Estrogen Receptor Expression in Autoimmune Myasthenia Gravis Endocrinology, May 1, 2005; 146(5): 2345 - 2353. [Abstract] [Full Text] [PDF]

				B. K. Dunn, D. L. Wickerham, and L. G. Ford Prevention of Hormone-Related Cancers: Breast Cancer J. Clin. Oncol., January 10, 2005; 23(2): 357 - 367. [Abstract] [Full Text] [PDF]

				B. Gold, F. Kalush, J. Bergeron, K. Scott, N. Mitra, K. Wilson, N. Ellis, H. Huang, M. Chen, R. Lippert, et al. Estrogen Receptor Genotypes and Haplotypes Associated with Breast Cancer Risk Cancer Res., December 15, 2004; 64(24): 8891 - 8900. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zheng, S. L. Articles by Gao, Y.-T. Search for Related Content PubMed PubMed Citation Articles by Zheng, S. L. Articles by Gao, Y.-T.