Journal Article
. 2016 Aug;48(9).
doi: 10.1152/physiolgenomics.00065.2016.

ESR1 and PGR polymorphisms are associated with estrogen and progesterone receptor expression in breast tumors

Daniel L Hertz 1 N Lynn Henry 2 Kelley M Kidwell 3 Dafydd Thomas 4 Audrey Goddard 5 Faouzi Azzouz 6 Kelly Speth 3 Lang Li 6 Mousumi Banerjee 7 Jacklyn N Thibert 2 Celina G Kleer 4 Vered Stearns 8 Daniel F Hayes 2 Todd C Skaar 6 James M Rae 9 
Affiliations
  • PMID: 27542969
  •     52 References
  •     2 citations

Abstract

Hormone receptor-positive (HR+) breast cancers express the estrogen (ERα) and/or progesterone (PgR) receptors. Inherited single nucleotide polymorphisms (SNPs) in ESR1, the gene encoding ERα, have been reported to predict tamoxifen effectiveness. We hypothesized that these associations could be attributed to altered tumor gene/protein expression of ESR1/ERα and that SNPs in the PGR gene predict tumor PGR/PgR expression. Formalin-fixed paraffin-embedded breast cancer tumor specimens were analyzed for ESR1 and PGR gene transcript expression by the reverse transcription polymerase chain reaction based Oncotype DX assay and for ERα and PgR protein expression by immunohistochemistry (IHC) and an automated quantitative immunofluorescence assay (AQUA). Germline genotypes for SNPs in ESR1 (n = 41) and PGR (n = 8) were determined by allele-specific TaqMan assays. One SNP in ESR1 (rs9322336) was significantly associated with ESR1 gene transcript expression (P = 0.006) but not ERα protein expression (P > 0.05). A PGR SNP (rs518162) was associated with decreased PGR gene transcript expression (P = 0.003) and PgR protein expression measured by IHC (P = 0.016), but not AQUA (P = 0.054). There were modest, but statistically significant correlations between gene and protein expression for ESR1/ERα and PGR/PgR and for protein expression measured by IHC and AQUA (Pearson correlation = 0.32-0.64, all P < 0.001). Inherited ESR1 and PGR genotypes may affect tumor ESR1/ERα and PGR/PgR expression, respectively, which are moderately correlated. This work supports further research into germline predictors of tumor characteristics and treatment effectiveness, which may someday inform selection of hormonal treatments for patients with HR+ breast cancer.

Keywords: AQUA; RT-PCR; estrogen receptor; genotype; immunohistochemistry; progesterone receptor.

Enhancing Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: Cotargeting Signaling Pathways.
Stephen R D Johnston.
J Natl Cancer Inst, 2015 Aug 08; 107(10). PMID: 26251289
Review.
Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.
J M Harvey, G M Clark, C K Osborne, D C Allred.
J Clin Oncol, 1999 May 20; 17(5). PMID: 10334533
Highly Cited.
Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Antonis C Antoniou, Christiana Kartsonaki, +183 authors, CIMBA.
Hum Mol Genet, 2011 May 20; 20(16). PMID: 21593217    Free PMC article.
The detection of ESR1/PGR/ERBB2 mRNA levels by RT-QPCR: a better approach for subtyping breast cancer and predicting prognosis.
Xin Du, Xiao-Qing Li, +2 authors, Yu-Mei Feng.
Breast Cancer Res Treat, 2013 Feb 12; 138(1). PMID: 23397283
The influence of ESR1 rs9340799 and ESR2 rs1256049 polymorphisms on prostate cancer risk.
Chenying Fu, Wen-Qi Dong, Ani Wang, Guozhen Qiu.
Tumour Biol, 2014 May 27; 35(8). PMID: 24859835
Association Between ESR1 PvuII, XbaI, and P325P Polymorphisms and Breast Cancer Susceptibility: A Meta-Analysis.
Yiming Zhang, Ming Zhang, +5 authors, Jian Jiang.
Med Sci Monit, 2015 Oct 06; 21. PMID: 26434778    Free PMC article.
Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy.
Yan Jin, Daniel F Hayes, +10 authors, Vered Stearns.
J Clin Oncol, 2008 Nov 20; 26(36). PMID: 19018086    Free PMC article.
Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer.
A Anghel, M Raica, +5 authors, E Popovici.
Neoplasma, 2010 May 01; 57(4). PMID: 20429621
Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes.
H W Deng, J Li, +4 authors, R R Recker.
Hum Genet, 1998 Dec 22; 103(5). PMID: 9860300
Quantitative analysis of estrogen receptor heterogeneity in breast cancer.
Gina G Chung, Maciej P Zerkowski, +2 authors, David L Rimm.
Lab Invest, 2007 Mar 06; 87(7). PMID: 17334408
Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers.
Andrew Berchuck, Joellen M Schildkraut, +11 authors, Georgia Chenevix-Trench.
Cancer Epidemiol Biomarkers Prev, 2004 Dec 16; 13(12). PMID: 15598772
Progesterone receptor modulates ERα action in breast cancer.
Hisham Mohammed, I Alasdair Russell, +22 authors, Jason S Carroll.
Nature, 2015 Jul 15; 523(7560). PMID: 26153859    Free PMC article.
Highly Cited.
Insights into the regulation of protein abundance from proteomic and transcriptomic analyses.
Christine Vogel, Edward M Marcotte.
Nat Rev Genet, 2012 Mar 14; 13(4). PMID: 22411467    Free PMC article.
Highly Cited. Review.
ESR1 ligand-binding domain mutations in hormone-resistant breast cancer.
Weiyi Toy, Yang Shen, +15 authors, Sarat Chandarlapaty.
Nat Genet, 2013 Nov 05; 45(12). PMID: 24185512    Free PMC article.
Highly Cited.
Association of estrogen receptor alpha gene polymorphisms with bone mineral density in Chinese women: a meta-analysis.
C-L Wang, X-Y Tang, +3 authors, Y-M Chen.
Osteoporos Int, 2006 Nov 08; 18(3). PMID: 17089081
Review.
HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants.
Lucas D Ward, Manolis Kellis.
Nucleic Acids Res, 2011 Nov 09; 40(Database issue). PMID: 22064851    Free PMC article.
Highly Cited.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), C Davies, +11 authors, R Peto.
Lancet, 2011 Aug 02; 378(9793). PMID: 21802721    Free PMC article.
Highly Cited.
Association of +331G/A PgR polymorphism with susceptibility to female reproductive cancer: evidence from a meta-analysis.
Sanjib Chaudhary, Aditya K Panda, Dipti Ranjan Mishra, Sandip K Mishra.
PLoS One, 2013 Jan 26; 8(1). PMID: 23349706    Free PMC article.
Association between polymorphisms in the progesterone receptor gene and endometriosis.
Susan A Treloar, Zhen Zhen Zhao, +5 authors, Grant W Montgomery.
Mol Hum Reprod, 2005 Aug 30; 11(9). PMID: 16126772
Meta-analysis of genome-wide association for migraine in six population-based European cohorts.
Lannie Ligthart, Boukje de Vries, +26 authors, Dorret I Boomsma.
Eur J Hum Genet, 2011 Mar 31; 19(8). PMID: 21448238    Free PMC article.
Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen.
Werner Schroth, Matthew P Goetz, +19 authors, Hiltrud Brauch.
JAMA, 2009 Oct 08; 302(13). PMID: 19809024    Free PMC article.
Highly Cited.
Estrogen receptor genotypes and haplotypes associated with breast cancer risk.
Bert Gold, Francis Kalush, +15 authors, Kenneth Offit.
Cancer Res, 2004 Dec 18; 64(24). PMID: 15604249
Tamoxifen in the treatment of breast cancer.
C K Osborne.
N Engl J Med, 1998 Nov 26; 339(22). PMID: 9828250
Highly Cited. Review.
Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk.
Sara Lindström, Deborah J Thompson, +42 authors, Rulla M Tamimi.
Nat Commun, 2014 Oct 25; 5. PMID: 25342443    Free PMC article.
Tissue microarrays (TMAs) for high-throughput molecular pathology research.
A Nocito, J Kononen, O P Kallioniemi, G Sauter.
Int J Cancer, 2001 Oct 23; 94(1). PMID: 11668471
PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers.
Roy R L Bastien, Álvaro Rodríguez-Lescure, +29 authors, Miguel Martín.
BMC Med Genomics, 2012 Oct 06; 5. PMID: 23035882    Free PMC article.
Highly Cited.
Estrogen receptor alpha (ERS1) SNPs c454-397T>C (PvuII) and c454-351A>G (XbaI) are risk biomarkers for breast cancer development.
Klesia Pirola Madeira, Renata Dalmaschio Daltoé, +3 authors, Ian Victor Silva.
Mol Biol Rep, 2014 Jun 15; 41(8). PMID: 24928087
Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25.
Laura Fejerman, Nasim Ahmadiyeh, +24 authors, Elad Ziv.
Nat Commun, 2014 Oct 21; 5. PMID: 25327703    Free PMC article.
Highly Cited.
CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8.
Matthew P Goetz, Vera J Suman, +14 authors, James N Ingle.
Clin Cancer Res, 2012 Dec 06; 19(2). PMID: 23213055    Free PMC article.
Roles of the ER-α36-EGFR/HER2 positive regulatory loops in tamoxifen resistance.
Li Yin, Zhao-Yi Wang.
Steroids, 2016 Feb 18; 111. PMID: 26884313
Review.
Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer.
N Lynn Henry, Todd C Skaar, +13 authors, David A Flockhart.
Breast Cancer Res Treat, 2013 Apr 03; 138(3). PMID: 23546553    Free PMC article.
Estrogen receptor genotype is associated with risk of venous thromboembolism during tamoxifen therapy.
Adedayo A Onitilo, Catherine A McCarty, +8 authors, Yan Jin.
Breast Cancer Res Treat, 2008 Dec 17; 115(3). PMID: 19082882
Progesterone receptor polymorphisms and risk of breast cancer: results from two Australian breast cancer studies.
Sharon E Johnatty, Amanda B Spurdle, +5 authors, Kathleen Cuningham Consortium for Research in Familial Breast Cancer.
Breast Cancer Res Treat, 2007 Jun 27; 109(1). PMID: 17592773
Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover.
Steffi Oesterreich, N Lynn Henry, +14 authors, David A Flockhart.
Breast Cancer Res Treat, 2015 Nov 06; 154(2). PMID: 26536870    Free PMC article.
Association between the ESR1 -351A>G single nucleotide polymorphism (rs9340799) and adolescent idiopathic scoliosis: a systematic review and meta-analysis.
Suzan Chen, Linlu Zhao, +2 authors, Eugene K Wai.
Eur Spine J, 2014 Aug 01; 23(12). PMID: 25077943
Systematic Review.
Standardization of estrogen receptor measurement in breast cancer suggests false-negative results are a function of threshold intensity rather than percentage of positive cells.
Allison W Welsh, Christopher B Moeder, +5 authors, David L Rimm.
J Clin Oncol, 2011 Jun 29; 29(22). PMID: 21709197    Free PMC article.
Classification of breast cancer using genetic algorithms and tissue microarrays.
Marisa Dolled-Filhart, Lisa Rydén, +4 authors, David L Rimm.
Clin Cancer Res, 2006 Nov 07; 12(21). PMID: 17085660
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Development and verification of the PAM50-based Prosigna breast cancer gene signature assay.
Brett Wallden, James Storhoff, +16 authors, Joel S Parker.
BMC Med Genomics, 2015 Aug 25; 8. PMID: 26297356    Free PMC article.
Highly Cited.
Genetic effects of common polymorphisms in estrogen receptor alpha gene on osteoarthritis: a meta-analysis.
Hecheng Ma, Weiqian Wu, +2 authors, Yubao Gong.
Int J Clin Exp Med, 2015 Nov 10; 8(8). PMID: 26550281    Free PMC article.
Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer.
N Lynn Henry, Faouzi Azzouz, +10 authors, Anna Maria Storniolo.
J Clin Oncol, 2012 Feb 15; 30(9). PMID: 22331951    Free PMC article.
Highly Cited.
Comprehensive molecular portraits of human breast tumours.
Cancer Genome Atlas Network.
Nature, 2012 Sep 25; 490(7418). PMID: 23000897    Free PMC article.
Highly Cited.
Development of a robust RNA-based classifier to accurately determine ER, PR, and HER2 status in breast cancer clinical samples.
Timothy R Wilson, Yuanyuan Xiao, +13 authors, Mark R Lackner.
Breast Cancer Res Treat, 2014 Oct 23; 148(2). PMID: 25338319    Free PMC article.
Association between Estrogen Receptor-α Gene XbaI and PvuII Polymorphisms and Periodontitis Susceptibility: A Meta-Analysis.
Hong Weng, Chao Zhang, +4 authors, Yu-Ming Niu.
Dis Markers, 2015 Dec 22; 2015. PMID: 26688601    Free PMC article.
Review.
Effect of hormone replacement therapy on plasma lipoproteins and apolipoproteins, endothelial function and myocardial perfusion in postmenopausal women with estrogen receptor-alpha IVS1-397 C/C genotype and established coronary artery disease.
Ayse Emre, Sinan Sahin, +5 authors, Birsen Ersek.
Cardiology, 2006 Apr 14; 106(1). PMID: 16612068
Indications of clinical and genetic predictors for aromatase inhibitors related musculoskeletal adverse events in Chinese Han women with breast cancer.
Jingxuan Wang, Kangping Lu, +12 authors, Qingyuan Zhang.
PLoS One, 2013 Jul 31; 8(7). PMID: 23894347    Free PMC article.
Activating ESR1 mutations in hormone-resistant metastatic breast cancer.
Dan R Robinson, Yi-Mi Wu, +22 authors, Arul M Chinnaiyan.
Nat Genet, 2013 Nov 05; 45(12). PMID: 24185510    Free PMC article.
Highly Cited.
Progesterone receptor PROGINS and +331G/A polymorphisms confer susceptibility to ovarian cancer: a meta-analysis based on 17 studies.
Ting Liu, Lilan Chen, +7 authors, Wen Di.
Tumour Biol, 2013 Nov 08; 35(3). PMID: 24197980
Human Genetic Variability Contributes to Postoperative Morphine Consumption.
Manuela De Gregori, Luda Diatchenko, +19 authors, Massimo Allegri.
J Pain, 2016 Feb 24; 17(5). PMID: 26902643
ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer.
Brian Leyland-Jones, Kathryn P Gray, +20 authors, BIG 1-98 Collaborative Group.
Breast Cancer Res Treat, 2015 Nov 23; 154(3). PMID: 26590813    Free PMC article.
Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease.
David M Herrington, Timothy D Howard, +6 authors, Eugene R Bleecker.
N Engl J Med, 2002 Mar 29; 346(13). PMID: 11919305
Significant role of estrogen and progesterone receptor sequence variants in gallbladder cancer predisposition: a multi-analytical strategy.
Anshika Srivastava, Kiran Lata Sharma, +2 authors, Balraj Mittal.
PLoS One, 2012 Jul 19; 7(7). PMID: 22808109    Free PMC article.
The prognostic significance of estrogen and progesterone receptors in grade I and II endometrioid endometrial adenocarcinoma: hormone receptors in risk stratification.
Jun Guan, Liying Xie, +4 authors, Xiaojun Chen.
J Gynecol Oncol, 2018 Nov 28; 30(1). PMID: 30479097    Free PMC article.
A Closer Look at Estrogen Receptor Mutations in Breast Cancer and Their Implications for Estrogen and Antiestrogen Responses.
Léa Clusan, Pascale Le Goff, Gilles Flouriot, Farzad Pakdel.
Int J Mol Sci, 2021 Jan 17; 22(2). PMID: 33451133    Free PMC article.
Review.