Skip to main content

Advertisement

SpringerLink
Log in

Progesterone Receptor (PGR) Gene Variants Associated with Breast Cancer and Associated Features: a Case-Control Study

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Insofar as altered estrogen receptor-progesterone receptor (PR) expression contribute to breast cancer pathogenesis, previous studies examined the association of genetic variation in PR gene (PGR) with breast cancer, but with mixed outcome. We evaluated the association between PGR variants, and breast cancer and associated features. A retrospective case-control study involving 183 female breast cancer patients, and 222 control women. PGR genotyping was done by real-time PCR. Minor allele frequencies of rs1042838, rs590688, and rs10895068 PGR gene polymorphisms were significantly higher in breast cancer patients compared to controls. Patients carrying rs1042838 G/T, rs590688 C/C, and rs10895068 G/A genotypes had higher risk of breast cancer, while carriage of rs3740753 G/G genotype was associated with marginal reduction in breast cancer risk. In addition, carriage of rs1042839, rs3740753, and rs10895068 minor allele was associated with Her2 status, while rs3740753 and rs10895068 were associated with effective hormone replacement therapy. Furthermore, carriage of rs10895068 minor allele in breast cancer women were also associated with age at first pregnancy, hormone receptor (RH) status, and previous use of oral contraceptives. PGR haploview analysis documented moderate-strong linkage disequilibrium (non-random association of alleles at different loci) between 7 of the 8 tested PGR SNPs, thus allowing construction of 7-locus PGR haplotypes. Two haplotypes, ATGCCGA and GTGCCGA, both containing rs590688, were positively associated with breast cancer, thus assigning a breast cancer-susceptible nature to these haplotypes. PGR rs1042838, rs590688, and rs10895068, and ATGCCGA and GTGCCGA haplotypes are related with increased breast cancer susceptibility in Tunisian women.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fan L, Goss PE, Strasser-Weippl K (2015) Current status and future projections of breast cancer in Asia. Breast Care (Basel) 10:372–378. https://doi.org/10.1007/s10552-014-0491-2

    Article  Google Scholar 

  2. Abdulrahman GO Jr, Rahman GA (2012) Epidemiology of breast cancer in Europe and Africa. J Cancer Epidemiol 2012:915610. https://doi.org/10.1155/2012/915610

    Article  PubMed  Google Scholar 

  3. Mojgan H, Massoud H, Ahmad E (2012) ERCC1 intron 1 was associated with breast cancer risk. Arch Med Sci 8:655–658. https://doi.org/10.5114/aoms.2012.30289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gallegos MP, Figuera LE, Ramos MC, Salas E, Puebla AM, Peralta V, Gaecia JE, Davalos IP, Zúñiga GM (2014) The association between the 844ins68 polymorphism in the CBS gene and breast cancer. Arch Med Sci 10:1214–1224. https://doi.org/10.5114/aoms.2014.47830

    Article  CAS  Google Scholar 

  5. Gómez Flores-Ramos L, Escoto-De Dios A, Puebla-Pérez AM, Figuera-Villanueva LE, Ramos-Silva A, Ramírez-Patiño R, Delgado-Saucedo JI, Salas-González E et al (2013) Association of the tumor necrosis factor-alpha –308G>A polymorphism with breast cancer in Mexican women. Genet Mol Res 12:5680–5693. https://doi.org/10.4238/2013

    Article  PubMed  Google Scholar 

  6. Xu YL, Sun Q, Shan GL, Zhang J, Liao HB, Li SY, Jiang J, Shao ZM et al (2012) A case-control study on risk factors of breast cancer in China. Arch Med Sci 8:303–309. https://doi.org/10.5114/aoms.2012.28558

    Article  PubMed  PubMed Central  Google Scholar 

  7. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  CAS  Google Scholar 

  8. Nyante SJ, Gammon MD, Kaufman JS, Bensen JT, Lin DY, Barnholtz-Sloan JS, Hu Y, He Q, Luo J, Millikan RC (2015) Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects. Cancer Causes Control 26:121–131. https://doi.org/10.1007/s10552-014-0491-2

    Article  PubMed  Google Scholar 

  9. Eiró N, Fernandez-Garcia B, Vázquez J, Del Casar JM, González LO, Vizoso FJ (2015) A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer. Oncoimmunology 4:e992222

    Article  Google Scholar 

  10. Hawkins RA, White G, Bundred NJ, Dixon JM, Miller WR, Stewart HJ, Forrest AP (1987) Prognostic significance of oestrogen and progestogen receptor activities in breast cancer. Br J Surg 74:1009–1013

    Article  CAS  Google Scholar 

  11. Savouret JF, Misrahi M, Milgrom E (1990) Molecular action of progesterone. Int J BioChemiPhysics 22:579–594

    Article  CAS  Google Scholar 

  12. Graham JD, Clarke CL (2002) Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells. Breast Cancer Res 4:187–190

    Article  CAS  Google Scholar 

  13. Mani SK, Oyola MG (2012) Progesterone signaling mechanisms in brain and behavior. Front Endocrinol (Lausanne) 3:7. https://doi.org/10.3389/fendo.2012.00007

    Article  CAS  Google Scholar 

  14. Fisher B, Redmond C, Fisher ER, Caplan R (1988) Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: findings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol 6:1076–1087

    Article  CAS  Google Scholar 

  15. Mote PA, Bartow S, Tran N, Clarke CL (2002) Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res Treat 72:163–172

    Article  CAS  Google Scholar 

  16. Gabriel CA, Mitra N, Demichele A, Rebbeck T (2013) Association of progesterone receptor gene (PGR) variants and breast cancer risk in African American women. Breast Cancer Res Treat 139:833–843. https://doi.org/10.1007/s10549-013-2592-0

    Article  CAS  PubMed  Google Scholar 

  17. Pooley KA, Healey CS, Smith PL, Pharoah PD, Thompson D, Tee L, West J, Jordan C et al (2006) Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach. Cancer Epidemiol Biomark Prev 15:675–682

    Article  CAS  Google Scholar 

  18. Pearce CL, Hirschhorn JN, Wu AH, Burtt NP, Stram DO, Young S, Kolonel LN, Henderson BE et al (2005) Clarifying the PROGINS allele association in ovarian and breast cancer risk: a haplotype-based analysis. J Natl Cancer Inst 97:51–59

    Article  CAS  Google Scholar 

  19. Gold B, Kalush F, Bergeron J, Scott K, Mitra N, Wilson K, Ellis N, Huang H et al (2004) Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 64:8891–8900

    Article  CAS  Google Scholar 

  20. Johnatty SE, Spurdle AB, Beesley J, Chen X, Hopper JL, Duffy DL, Chenevix-Trench G (2008) Progesterone receptor polymorphisms and risk of breast cancer: results from two Australian breast cancer studies. Breast Cancer Res Treat 109:91–99

    Article  CAS  Google Scholar 

  21. Fernandez LP, Milne RL, Barroso E, Cuadros M, Arias JI, Ruibal A, Benitez J, Ribas G (2006) Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: a Spanish case control study. Int J Cancer 119:467–471

    Article  CAS  Google Scholar 

  22. Romano A, Delvoux B, Fischer DC, Groothuis P (2007) The PROGINS polymorphism of the human progesterone receptor diminishes the response to progesterone. J Mol Endocrinol 38:331–350

    Article  CAS  Google Scholar 

  23. Clendenen T, Zeleniuch-Jacquotte A, Wirgin I, Koenig KL, Afanasyeva Y, Lundin E, Arslan AA, Axelsson T et al (2013) Genetic variants in hormone-related genes and risk of breast cancer. PLoS One 8:e69367. https://doi.org/10.1371/journal.pone.0069367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Diergaarde B, Potter JD, Jupe ER, Manjeshwar S, Shimasaki CD, Pugh TW, Defreese DC, Gramling BA et al (2008) Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomark Prev 17:1751–1759. https://doi.org/10.1158/1055-9965.EPI-08-0168

    Article  CAS  Google Scholar 

  25. Reding KW, Li CI, Weiss NS, Chen C, Carlson CS, Duggan D, Thummel KE, Daling JR, Malone KE (2009) Genetic variation in the progesterone receptor and metabolism pathways and hormone therapy in relation to breast cancer risk. Am J Epidemiol 170:1241–1249. https://doi.org/10.1093/aje/kwp298

    Article  PubMed  PubMed Central  Google Scholar 

  26. Spurdle AB, Hopper JL, Chen X, McCredie MR, Giles GG, Venter DJ, Southey MC, Chenevix-Trench G (2002) The progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of breast cancer in Australian women. Cancer Epidemiol Biomark Prev 11:439–443

    CAS  Google Scholar 

  27. Gaudet MM, Milne RL, Cox A, Camp NJ, Goode EL, Humphreys MK, Dunning AM, Morrison J et al (2009) Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium. Cancer Epidemiol Biomark Prev 18:1610–1616. https://doi.org/10.1158/1055-9965

    Article  CAS  Google Scholar 

  28. Zhang B, Beeghly-Fadiel A, Long J, Zheng W (2011) Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol 12:477–488. https://doi.org/10.1016/S1470-2045(11)70076-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De Vivo I, Hankinson SE, Colditz GA, Hunter DJ (2004) The progesterone receptor Val660-->Leu polymorphism and breast cancer risk. Breast Cancer Res 6:R636–R639

    Article  Google Scholar 

  30. Huggins GS, Wong JY, Hankinson SE, De Vivo I (2006) GATA5 activation of the progesterone receptor gene promoter in breast cancer cells is influenced by the +331G/A polymorphism. Cancer Res 66:1384–1390

    Article  CAS  Google Scholar 

  31. Feigelson HS, Rodriguez C, Jacobs EJ, Diver WR, Thun MJ, Calle EE (2004) No association between the progesterone receptor gene +331G/A polymorphism and breast cancer. Cancer Epidemiol Biomark Prev 13:1084–1085

    Article  CAS  Google Scholar 

  32. Yu KD, Chen AX, Shao ZM (2010) No association between a progesterone receptor gene promoter polymorphism (+331G>A) and breast cancer risk in Caucasian women: evidence from a literature-based meta-analysis. Breast Cancer Res Treat 122:853–858

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Sami Limem for this constant help and support. The study was partially supported by a grant from the Islamic Development Bank (Jeddah, Saudi Arabia).

Author information

Authors and Affiliations

  1. Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy of Monastir, University of Monastir, Monastir, Tunisia

    Rabeb M. Ghali, Hanen H. Jrah & Touhami Mahjoub

  2. Faculty of Sciences of Bizerte, University of Carthage, Tunis, Tunisia

    Rabeb M. Ghali

  3. Faculty of Sciences, Universite’ de Tunis El Manar, Campus Universitaire, 2092 Manar II, Tunis, Tunisia

    Maryam A. Al-Mutawa, Bashayer H. Ebrahim & Wassim Y. Almawi

  4. Department of Clinical Oncology, CHU Fattouma Bourguiba, Monastir, Tunisia

    Sonia Zaied & Hanen Bhiri

  5. Department of Surgery, CHU Farhat Hached, Sousse, Tunisia

    Fahmi Hmila

Authors
  1. Rabeb M. Ghali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam A. Al-Mutawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bashayer H. Ebrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanen H. Jrah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sonia Zaied
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hanen Bhiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fahmi Hmila
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Touhami Mahjoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wassim Y. Almawi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RMG Specimen processing, drafting of manuscript. MAA Genotyping. BHE Genotyping. HHJ Data analysis. SZ Patient selection and referral. HB Patient selection and referral. FH Patient selection and referral. TM Control women selection and referral. WYA Project leader; finalizing analysis and manuscript.

Corresponding author

Correspondence to Wassim Y. Almawi.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghali, R.M., Al-Mutawa, M.A., Ebrahim, B.H. et al. Progesterone Receptor (PGR) Gene Variants Associated with Breast Cancer and Associated Features: a Case-Control Study. Pathol. Oncol. Res. 26, 141–147 (2020). https://doi.org/10.1007/s12253-017-0379-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0379-z

Keywords

Search

Navigation