The estrogen effect; clinical and histopathological evidence of dichotomous influences in dogs with spontaneous mammary carcinomas

Autoři: Karin U. Sorenmo aff001;  Amy C. Durham aff002;  Enrico Radaelli aff003;  Veronica Kristiansen aff004;  Laura Peña aff005;  Michael H. Goldschmidt aff003;  Darko Stefanovski aff006
Působiště autorů: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff001;  Penn Vet Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff002;  Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America aff003;  Department of Companion Animal Clinical Sciences, Veterinary Medicine and Biosciences, Norwegian University of Life Sciences, Oslo, Norway aff004;  Department of Animal Medicine, Surgery and Pathology, Veterinary School, Complutense University of Madrid, Madrid, Spain aff005;  Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania - New Bolton Center, Kennett Square, Pennsylvania, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224504


The purpose of this study was to investigate the associations and explore the relationships between hormonal factors (serum estrogen, estrogen receptors and ovariohysterectomy) and other clinical/histological prognostic factors and their impact on outcome in dogs with mammary carcinomas. Data from two separate prospective studies on dogs with spontaneous mammary carcinomas were used for this research. All dogs underwent standardized diagnostic testing, staging, surgery and follow-up examinations. Serum estrogen was analyzed by competitive enzyme immunoassay or radioimmunoassay, and tumor estrogen receptor (ER) expression was analyzed by immunohistochemistry. A total of 159 dogs were included; 130 were spayed and 29 remained. High serum estrogen was associated with an overall longer time to metastasis (p = 0.021). When stratifying based on spay group, the effect was only significant in spayed dogs, (p = 0.019). Positive tumor ER expression was also associated with a longer time to metastasis (p = 0.025), but similar to above, only in dogs that were spayed (p = 0.049). Further subgroup analysis revealed that high serum estrogen was significantly associated with improved survival in dogs with ER positive tumors, but only in spayed dogs (p = 0.0052). Interestingly, the effect of spaying was the opposite in dogs with ER negative tumors; here, intact dogs with high serum estrogen but ER negative tumors had a significantly longer time to metastasis (p = 0.036). Low serum estrogen was associated with increased risk for the development of non-mammary tumors in the post-operative period (p = 0.012). These results highlight the dual effect of estrogen in cancer: Estrogen acts as a pro-carcinogen in ER positive mammary tumors, but a may have a protective effect in ER negative tumors, potentially via non-receptor mechanisms. The latter is supported by the decreased risk for non-mammary tumors in dogs with high serum estrogen, and explains the increased incidence of certain non-mammary tumors in in dogs spayed at an early age.

Klíčová slova:

Breast cancer – Carcinomas – Dogs – Estrogens – Immunohistochemistry techniques – Metastasis – Surgical oncology – Veterinary diagnostics


1. Schneider R, Dorn CR, Taylor DON: Factors influencing canine mammary cancer development and postsurgical survival. J Natl Cancer Inst. 1969;43(6):1249–61. 4319248

2. Santen RJ, Boyd NF, Chlebowski RT, Cummings S, Cuzick J, Dowsett M, et al. Critical assessment of new risk factors for breast cancer: considerations for development of an improved risk prediction model. Endocr Relat cancer. 2007;14:169–87. doi: 10.1677/ERC-06-0045 17639036

3. Feinleib M. Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst. 1968;41:315–329. 5671283

4. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer (1). N Engl J Med. 1992;327:319–28. doi: 10.1056/NEJM199207303270505 1620171

5. Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst. 1995;87:1681–5. doi: 10.1093/jnci/87.22.1681 7473816

6. Feigelson HS, Henderson BE. Estrogens and breast cancer. Carcinogenesis. 1996;17:2279–84. doi: 10.1093/carcin/17.11.2279 8968038

7. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer [published erratum appears in Lancet 1997;350:1484]. Lancet. 1997;350:1047–59. 10213546

8. Key T, Appleby P, Barnes I, Reeves G. Endogenous hormones and breast cancer collaborative group endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606–616.

9. Rock CL, Flatt SW, Laughlin GA, Gold EB, Thomson CA, Natarjan L et al. Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:614–20. doi: 10.1158/1055-9965.EPI-07-0761 18323413

10. Walker K, Bratton DJ, Frost C. Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis. British Journal of Cancer. 2011;105:1451–1457. doi: 10.1038/bjc.2011.358 21915119

11. Illera JC, Perez-Alenza MD, Nieto A, Jimenez MA, Silvan G, Dunner S. Steroids and receptors in canine mammary cancer. Steroids. 2006;71:541–8. doi: 10.1016/j.steroids.2005.11.007 16631217

12. Yaeger JD, Chapter 3: Endogenous Estrogens as carcinogens through metabolic activation. J Natl Cancer Institute Monogr. 2000;27:67–73.

13. Santen RJ, Yue Wei, Wang JP. Estrogen metabolites and breast cancer. Steroids. 2015;99:61–66. doi: 10.1016/j.steroids.2014.08.003 25168343

14. Yager JD. Mechanisms of estrogen carcinogenesis: The role of E2/E1-quinone metabolites suggest new approaches to preventive intervention—A review. Steroids. 2015;99:56–60. doi: 10.1016/j.steroids.2014.08.006 25159108

15. Yue W, Yager JD, Wang Ji-P, Jupe ER, Santen RJ. Estrogen receptor-dependent and independent mechanisms of breast carcinogenesis. Steroids. 2013;78:161–170. doi: 10.1016/j.steroids.2012.11.001 23178278

16. Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol. 2006;102:89–96. doi: 10.1016/j.jsbmb.2006.09.004 17113977

17. Okoh V, Deoraj A, Roy D. Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer. Biochim Biophys Acta. 2011;1815:115–133. doi: 10.1016/j.bbcan.2010.10.005 21036202

18. Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A'hern R, Crowder RJ, et al. Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women. J Clin Oncol. 2010; 28:1161–1167. doi: 10.1200/JCO.2009.23.9616 20124184

19. Haynes BP, Viale G, Galimberti V, Rotmensz N, Gibelli B, A’Hern R, et al Expression of key oestrogen-regulated genes differs substantially across the menstrual cycle in oestrogen receptor-positive primary breast cancer. Breast Cancer Res Treat. 2013;138:157–165. doi: 10.1007/s10549-013-2426-0 23378065

20. Haakensen VD, Bjøro T, Lüders T, Riis M, Bukholm IK, Kristensen VN, et al. Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas. BMC Cancer. 2011;11:332. doi: 10.1186/1471-2407-11-332 21812955

21. Jordan VC. The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer. 2015;22:1–56.

22. Kumler I, Knopp AS, Jessing CAR, Ejlertsen B. Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant. ESMO open 2016;1(4):e000062. doi: 10.1136/esmoopen-2016-000062 27843622

23. Shah R, O’Regan RM. Adjuvant Endocrine Therapy. Cancer Treat Res. 2018;173:15–29. doi: 10.1007/978-3-319-70197-4_2 29349755

24. Rugo HS, Rumble RB, Macrae E et al (2016) Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. J Clin Oncol 34:3069–3103. 27217461

25. Jordan VC, Brodie AM. Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer. Steroids. 2007;72:7–25. doi: 10.1016/j.steroids.2006.10.009 17169390

26. Calhoun BC, Collins LC. Predictive markers in breast cancer: An update on ER and HER2 testing and reporting. Semin Diagn Pathol. 2015;32:362–9. doi: 10.1053/j.semdp.2015.02.011 25770732

27. Root Kustritz M V. Managing the reproductive cycle in the bitch. Veterinary Clinics of North America: Small Animal Practice. 2012;42:423–437. doi: 10.1016/j.cvsm.2012.01.012 22482809

28. Kristiansen V, Pena L, Cordova LD, Illera J, Skjerve E, Breen AM, et al. Effect of ovariohysterectomy at the time of tumor removal in dogs with mammary carcinomas; a randomized clinical trial. J Vet Intern Med. 2016;30 (1):230–41. doi: 10.1111/jvim.13812 26687731

29. Sorenmo KU, Durham AC, Kristiansen V, Pena L, Goldschmidt MH. Developing and testing prognostic bio-scoring systems for canine mammary carcinomas. Vet Comp Oncol. 2019; doi: 10.1111/vco.12509 31099972

30. Goldschmidt M, Pena L, Rasotto R, Zappulli V. Classification and grading of canine mammary tumors. Vet Pathol. 2011;48:117–131. doi: 10.1177/0300985810393258 21266722

31. Pena L, De Andres PJ, Clemente M, Cuesta P, Perez-Alenza MD. Prognostic value of histological grading in noninflammatory canine mammary carcinomas in a prospective study with two-year follow-up: Relationship with clinical and histological characteristics. Vet Pathol. 2013;50:94–105. doi: 10.1177/0300985812447830 22688585

32. Pena L, Gama A, Goldschmidt MH, Abadie J, Benazzi C, Castagaro M et al. Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry. Vet Pathol. 2014;51:127–145. doi: 10.1177/0300985813509388 24227007

33. Gilles GE, McArthur S. Estrogen actions in the brain and the basis for differential actions in men and women: a case for sex-specific medicines. Pharmacol Rev. 2010;62:155–198. doi: 10.1124/pr.109.002071 20392807

34. Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K et al. Aromatase-a brief overview. Annu Rev Physiol. 2002;64:93–127. doi: 10.1146/annurev.physiol.64.081601.142703 11826265

35. Blackmore J, Naftolin F. Aromatase: Contributions to physiology and disease in women and men. Physiology (Bethesda). 2016;31:258–269.

36. Patel S, Homaei A, Butchi Raju A, Ranjan Mehr B. Estrogen: The necessary evil for human health and ways to tame it. Biomedicine & Pharmacotherapy. 2018;102:403–411

37. Spain VC, Scarlett J, Houpt AK. Long-term risks and benefits of early-age gonadectomy in dogs. Am Vet Med Assoc. 2004;224:380–387.

38. Gregory SP. Developments in the understanding of the pathophysiology of urethral sphincter mechanism incompetence in the bitch. British Veterinary Journal. 1994;150:135–150. doi: 10.1016/S0007-1935(05)80222-2 8025846

39. Slauterbeck JR, Pankrantz K, Xu KT, Bozeman SC, Hardy DM. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clin Orthop Relat Res. 2004;429:301–305.

40. Hoffman JM, Creevy KE, Promislow DE. Reproductive Capability is associated with lifespan and cause of death in companion dogs. PLoS One. 2013 8(4): e61082. doi: 10.1371/journal.pone.0061082 23613790

41. Bennett PF, Taylor R, Williamson P. Demographic risk factors for lymphoma in Australian dogs: 6201 cases. J Vet Intern Med. 2018;32:2054–2060. doi: 10.1111/jvim.15306 30307659

42. Smith AN. The role of neutering in cancer development. Vet Clin North Am Small Anim Pract. 2014;44:965–75. doi: 10.1016/j.cvsm.2014.06.003 25174910

43. Hart BL, Hart LA, Thigpen AP, Willits NH. Long-term health effects of neutering dogs: comparison of Labrador Retrievers with Golden Retrievers. PLoS One. 2014;14;9(7):e102241. doi: 10.1371/journal.pone.0102241 25020045

44. Zink MC, Farhoody P, Elser SE. Evaluation of the risk and age of onset of cancer and behavioral disorders in gonadectomized Vizslas. J Am Vet Med Assoc. 2014;244:309–319. doi: 10.2460/javma.244.3.309 24432963

45. Gama A, Alves A, Schmitt F. Identification of molecular phenotypes in canine mammary carcinomas with clinical implications: application of the human classification. Virchows Arch. 2008;453:123–132. doi: 10.1007/s00428-008-0644-3 18677512

46. Im KS, Kim IH, Kim NH, Lim HY, Kim JH, Sur JH. Breed-related differences in altered BRCA1 expression, phenotype and subtype in malignant canine mammary tumors. Vet J. 2013;195:366–372. doi: 10.1016/j.tvjl.2012.07.014 22901454

47. Kristiansen VM, Nodtvedt A, Breen AM, Langeland M, Teigen J, Goldschmidt M, et al. Effect of ovariohysterectomy at the time of tumor removal in dogs with benign mammary tumors and hyperplastic lesions: a randomized controlled clinical trial. J Vet Intern Med. 2013;27:935–942. doi: 10.1111/jvim.12110 23701181

48. Zhang FF, Haslam DE, Terry MB, Knight JA, Andrulis IL, Daly MB, et al. Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry. Cancer. 2017;123:2070–2079. doi: 10.1002/cncr.30615 28263368

49. Mourits MJ, deVries EG, Wilemse PH, et al. Ovarian cysts in women receiving tamoxifen for breast cancer. Br J Cancer. 1999;79:1761–4. doi: 10.1038/sj.bjc.6690280 10206289

50. Cohen I, Figer A, Tepper R, Shapira J, Altaras MM, Yigael D, et al. Ovarian overstimulation and cystic formation in premenopausal tamoxifen exposure: comparison between tamoxifen-treated and nontreated breast cancer patients. Gynecol Oncol. 1999;72:202–207. doi: 10.1006/gyno.1998.5201 10021302

51. Geisler J, N King, M Dowsett, L Ottestad, L Lundgren, P Walton, et al. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer. 1996;74:1286–1291. doi: 10.1038/bjc.1996.531 8883419

52. Duggan C, Stanczyk F, Campell K, Neuhouser ML, Baumgartner RN, Bernstein L. Associations of sex steroid hormones with mortality in women with breast cancer. Breast Cancer Res Treat. 2016;155:559–567. doi: 10.1007/s10549-016-3704-4 26865065

53. Haddow A, Watkinson JM, Paterson E, Koller PC. Influence of synthetic oestrogens on advanced malignant disease. Br Med J. 1944;2:393–398. doi: 10.1136/bmj.2.4368.393 20785660

54. DeSombre ER, Carbone PP, Jensen EV, McGuire WL, Wells SA Jr, Wittliff JL, et al. Special report. Steroid receptors in breast cancer. N Engl J Med. 1979;301(18):1011–2. doi: 10.1056/NEJM197911013011826 492228

55. Lonning PE. Additive endocrine therapy for advanced breast cancer-back to the future. Acta Oncol. 2009;302:774–780.

56. Jordan VC. The new biology of estrogen induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer. 2015;22: R1–31, doi: 10.1530/ERC-14-0448 25339261

57. Ariazi EA, Cunliffe HE, Lewis-Wambi JS, Slifker MJ, Willis AL, Ramos P, et al. Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time. Proc Natl Acad Sci USA. 2011;108:18879–86. doi: 10.1073/pnas.1115188108 22011582

58. Rocca W, Grossardt B, de Andrade M, Malkasian G, Melton LJ 3rd. Survival pattern after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol. 2006;7:821–828. doi: 10.1016/S1470-2045(06)70869-5 17012044

59. Parker WH, Broder MS, Chang E, Feskanich D, Farquhar C, Liu Z et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ health study. Obstet Gynecol. 2009;113:1027–37. doi: 10.1097/AOG.0b013e3181a11c64 19384117

60. Schwartz AG, Wenzlaff AS, Prysak GM, Murphy V, Cote ML, Brooks SC. Reproductive factors, hormone use, estrogen receptor expression and risk of non-small-cell lung cancer in women. J Clin Oncol. 2007;25:5785–5792. doi: 10.1200/JCO.2007.13.3975 18089876

61. Kreuzer M, Gerken M, Heinrich J, Kreienbrock L, Wichmann HE. Hormonal factors and risk of lung cancer among women? Int J Epidemiol. 2003;32:263–271. doi: 10.1093/ije/dyg064 12714547

62. Schabath MB, Wu X, Vassilopoulou-Sellin R, Vaporciyan AA, Spitz MR. Hormone replacement therapy and lung cancer risk: A case-control analysis. Clin Cancer Res. 2004;10:113–123. 14734459

63. Luo G, Zhang Y, Wang l, Huang Y, Yu Q, Guo P. Risk of colorectal cancer with hysterectomy and oophorectomy: A systematic review and meta-analysis. Int J Surg. 2016;34:88–95. doi: 10.1016/j.ijsu.2016.08.518 27568653

64. Jacobs EJ, White E, Weiss NS. Exogenous hormones, reproductive history, and colon cancer (Seattle, Washington, USA). Cancer Causes Control. 1994;5:359–366. 8080948

65. Haakensen VD, Bjøro T, Lüders T, Riis M, Bukholm IK, Kristensen VN, et al. Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas. BMC Cancer. 2011;11:332. doi: 10.1186/1471-2407-11-332 21812955

66. Calhoun BC, Collins LC. Predictive markers in breast cancer: An update on ER and HER2 testing and reporting. Semin Diagn Pathol. 2015;32:362–69, doi: 10.1053/j.semdp.2015.02.011 25770732

Článek vyšel v časopise


2019 Číslo 10