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Inter-Individual Variation in Response to Estrogen in Human Breast Explants

Abstract

Exposure to estrogen is strongly associated with increased breast cancer risk. While all women are exposed to estrogen, only 12% are expected to develop breast cancer during their lifetime. These women may be more sensitive to estrogen, as rodent models have demonstrated variability in estrogen sensitivity. Our objective was to determine individual variation in expression of estrogen receptor (ER) and estrogen-induced responses in the normal human breast. Human breast tissue from female donors undergoing reduction mammoplasty surgery were collected for microarray analysis of ER expression. To examine estrogen-induced responses, breast tissue from 23 female donors were cultured ex- vivo in basal or 10 nM 17β-estradiol (E2) media for 4 days. Expression of ER genes (ESR1 and ESR2) increased significantly with age. E2 induced consistent increases in global gene transcription, but expression of target genes AREG, PGR, and TGFβ2 increased significantly only in explants from nulliparous women. E2-treatment did not induce consistent changes in proliferation or radiation induced apoptosis. Responses to estrogen are highly variable among women and not associated with levels of ER expression, suggesting differences in intracellular signaling among individuals. The differences in sensitivity to E2-stimulated responses may contribute to variation in risk of breast cancer.

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Abbreviations

AREG:

amphiregulin

E2:

17β-estradiol

EGF:

Epidermal Growth Factor

ERB041, an ERβ agonist:

7-Ethenyl-2-(3- fluoro-4-hydroxyphenyl)-5-benzoaxazolol

ESR1:

estrogen receptor 1 gene

ESR2:

estrogen receptor 2 gene

ER:

estrogen receptor protein

ERα:

estrogen receptor alpha

ERβ:

Estrogen receptor beta

H2AX:

H2A.X varient histone

H&E:

hematoxylin and eosin stain

KRT18:

keratin 18 gene

P4:

progesterone

PCNA:

proliferating cell nuclear antigen

PGR:

progesterone receptor protein

PPT, an ERα agonist:

4,4’4”-(4’Propuyl-[1H]-pyrazole-1,2,4-triyl)trisphenol

PR:

progesterone receptor gene

RR:

relative risk

TDLU:

terminal ductal lobular unit

TGFβ2:

transforming growth factor beta 2 gene

TUNEL:

terminal deoxynucleotidyl transferase dUTP nick end labeling

References

  1. 1.

    Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276–85. https://doi.org/10.1056/nejm200101253440407.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Brinton LA, Hoover R, Fraumeni JF Jr. Reproductive factors in the aetiology of breast cancer. Br J Cancer. 1983;47(6):757–62. https://doi.org/10.1038/bjc.1983.128.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Brinton LA, Schairer C, Hoover RN, Fraumeni JF Jr. Menstrual factors and risk of breast cancer. Cancer Investig. 1988;6(3):245–54.

    CAS  Article  Google Scholar 

  4. 4.

    Dall GV, Britt KL. Estrogen effects on the mammary gland in early and late life and breast Cancer risk. Front Oncol. 2017;7:110. https://doi.org/10.3389/fonc.2017.00110.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. Jama. 2002;288(3):321–33.

    CAS  Article  Google Scholar 

  6. 6.

    MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, et al. Age at first birth and breast cancer risk. Bull World Health Organ. 1970;43(2):209–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Trichopoulos D, Hsieh CC, MacMahon B, Lin TM, Lowe CR, Mirra AP, et al. Age at any birth and breast cancer risk. Int J Cancer. 1983;31(6):701–4.

    CAS  Article  Google Scholar 

  8. 8.

    Albrektsen G, Heuch I, Hansen S, Kvale G. Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects. Br J Cancer. 2005;92(1):167–75. https://doi.org/10.1038/sj.bjc.6602302.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Lambe M, Hsieh CC, Chan HW, Ekbom A, Trichopoulos D, Adami HO. Parity, age at first and last birth, and risk of breast cancer: a population-based study in Sweden. Breast Cancer Res Treat. 1996;38(3):305–11.

    CAS  Article  Google Scholar 

  10. 10.

    Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S. Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. Proc Natl Acad Sci U S A. 1999;96(5):2520–5. https://doi.org/10.1073/pnas.96.5.2520.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Thordarson G, Jin E, Guzman RC, Swanson SM, Nandi S, Talamantes F. Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia? Carcinogenesis. 1995;16(11):2847–53. https://doi.org/10.1093/carcin/16.11.2847.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Sivaraman L, Stephens LC, Markaverich BM, Clark JA, Krnacik S, Conneely OM, et al. Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. Carcinogenesis. 1998;19(9):1573–81. https://doi.org/10.1093/carcin/19.9.1573.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Dunphy KA, Blackburn AC, Yan H, O'Connell LR, Jerry DJ. Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/− mice. Breast Cancer Res. 2008;10(3):R43. https://doi.org/10.1186/bcr2094.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lonning PE, Taylor PD, Anker G, Iddon J, Wie L, Jorgensen LM, et al. High-dose estrogen treatment in postmenopausal breast cancer patients heavily exposed to endocrine therapy. Breast Cancer Res Treat. 2001;67(2):111–6.

    CAS  Article  Google Scholar 

  15. 15.

    Coelingh Bennink HJ, Verhoeven C, Dutman AE, Thijssen J. The use of high-dose estrogens for the treatment of breast cancer. Maturitas. 2017;95:11–23. https://doi.org/10.1016/j.maturitas.2016.10.010.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Gruber CJ, Tschugguel W, Schneeberger C, Huber JC. Production and actions of estrogens. N Engl J Med. 2002;346(5):340–52. https://doi.org/10.1056/NEJMra000471.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87(3):905–31. https://doi.org/10.1152/physrev.00026.2006.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Yasar P, Ayaz G, User SD, Gupur G, Muyan M. Molecular mechanism of estrogen-estrogen receptor signaling. Reprod Med Biol. 2017;16(1):4–20. https://doi.org/10.1002/rmb2.12006.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Chang EC, Charn TH, Park SH, Helferich WG, Komm B, Katzenellenbogen JA, et al. Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol Endocrinol. 2008;22(5):1032–43. https://doi.org/10.1210/me.2007-0356.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Speirs V, Skliris GP, Burdall SE, Carder PJ. Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol. 2002;55(5):371–4. https://doi.org/10.1136/jcp.55.5.371.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Shoker BS, Jarvis C, Clarke RB, Anderson E, Hewlett J, Davies MP, et al. Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol. 1999;155(6):1811–5. https://doi.org/10.1016/s0002-9440(10)65498-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Gulbahce HE, Blair CK, Sweeney C, Salama ME. Quantification of estrogen receptor expression in Normal breast tissue in postmenopausal women with breast Cancer and association with tumor subtypes. Appl Immunohistochem Mol Morphol. 2017;25(8):548–52. https://doi.org/10.1097/pai.0000000000000337.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Shoker BS, Jarvis C, Sibson DR, Walker C, Sloane JP. Oestrogen receptor expression in the normal and pre-cancerous breast. J Pathol. 1999;188(3):237–44. https://doi.org/10.1002/(sici)1096-9896(199907)188:3<237::Aid-path343>3.0.Co;2-8.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Umekita Y, Souda M, Ohi Y, Rai Y, Sagara Y, Sagara Y, et al. Expression of estrogen receptor alpha and progesterone receptor in normal human breast epithelium. In Vivo. 2007;21(3):535–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Jerry DJ, Shull JD, Hadsell DL, Rijnkels M, Dunphy KA, Schneider SS, et al. Genetic variation in sensitivity to estrogens and breast cancer risk. Mamm Genome. 2018;29(1–2):24–37. https://doi.org/10.1007/s00335-018-9741-z.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Montero Girard G, Vanzulli SI, Cerliani JP, Bottino MC, Bolado J, Vela J, et al. Association of estrogen receptor-alpha and progesterone receptor a expression with hormonal mammary carcinogenesis: role of the host microenvironment. Breast Cancer Res. 2007;9(2):R22. https://doi.org/10.1186/bcr1660.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Aupperlee MD, Drolet AA, Durairaj S, Wang W, Schwartz RC, Haslam SZ. Strain-specific differences in the mechanisms of progesterone regulation of murine mammary gland development. Endocrinology. 2009;150(3):1485–94. https://doi.org/10.1210/en.2008-1459.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Shull JD, Dennison KL, Chack AC, Trentham-Dietz A. Rat models of 17beta-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention. Physiol Genomics. 2018;50(3):215–34. https://doi.org/10.1152/physiolgenomics.00105.2017.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Battersby S, Robertson BJ, Anderson TJ, King RJ, McPherson K. Influence of menstrual cycle, parity and oral contraceptive use on steroid hormone receptors in normal breast. Br J Cancer. 1992;65(4):601–7. https://doi.org/10.1038/bjc.1992.122.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Soderqvist G, von Schoultz B, Tani E, Skoog L. Estrogen and progesterone receptor content in breast epithelial cells from healthy women during the menstrual cycle. Am J Obstet Gynecol. 1993;168(3 Pt 1):874–9. https://doi.org/10.1016/s0002-9378(12)90837-6.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Roskelley CD, Desprez PY, Bissell MJ. Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc Natl Acad Sci U S A. 1994;91(26):12378–82. https://doi.org/10.1073/pnas.91.26.12378.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kass L, Erler JT, Dembo M, Weaver VM. Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. Int J Biochem Cell Biol. 2007;39(11):1987–94. https://doi.org/10.1016/j.biocel.2007.06.025.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Rosenblatt AE, Garcia MI, Lyons L, Xie Y, Maiorino C, Desire L, et al. Inhibition of the rho GTPase, Rac1, decreases estrogen receptor levels and is a novel therapeutic strategy in breast cancer. Endocr Relat Cancer. 2011;18(2):207–19. https://doi.org/10.1677/erc-10-0049.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Padro M, Louie RJ, Lananna BV, Krieg AJ, Timmerman LA, Chan DA. Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells. BMC Cancer. 2017;17(1):203. https://doi.org/10.1186/s12885-017-3140-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Clarke RB. Steroid receptors and proliferation in the human breast. Steroids. 2003;68(10–13):789–94. https://doi.org/10.1016/s0039-128x(03)00122-3.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Russo J, Ao X, Grill C, Russo IH. Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat. 1999;53(3):217–27.

    CAS  Article  Google Scholar 

  37. 37.

    Sokol ES, Miller DH, Breggia A, Spencer KC, Arendt LM, Gupta PB. Growth of human breast tissues from patient cells in 3D hydrogel scaffolds. Breast Cancer Res. 2016;18(1):19. https://doi.org/10.1186/s13058-016-0677-5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Eigeliene N, Harkonen P, Erkkola R. Effects of estradiol and medroxyprogesterone acetate on expression of the cell cycle proteins cyclin D1, p21 and p27 in cultured human breast tissues. Cell Cycle. 2008;7(1):71–80. https://doi.org/10.4161/cc.7.1.5102.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Eigeliene N, Harkonen P, Erkkola R. Effects of estradiol and medroxyprogesterone acetate on morphology, proliferation and apoptosis of human breast tissue in organ cultures. BMC Cancer. 2006;6:246. https://doi.org/10.1186/1471-2407-6-246.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Zhuang YH, Saaristo R, Ylikomi T. An in vitro long-term culture model for normal human mammary gland: expression and regulation of steroid receptors. Cell Tissue Res. 2003;311(2):217–26. https://doi.org/10.1007/s00441-002-0683-z.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Tanos T, Sflomos G, Echeverria PC, Ayyanan A, Gutierrez M, Delaloye JF, et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci Transl Med. 2013;5(182):182ra55. https://doi.org/10.1126/scitranslmed.3005654.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Vanoosthuyse V. Strengths and Weaknesses of the Current Strategies to Map and Characterize R-Loops. Noncoding RNA. 2018;4(2). https://doi.org/10.3390/ncrna4020009.

  43. 43.

    Belotserkovskii BP, Tornaletti S, D'Souza AD, Hanawalt PC. R-loop generation during transcription: formation, processing and cellular outcomes. DNA Repair (Amst). 2018;71:69–81. https://doi.org/10.1016/j.dnarep.2018.08.009.

    CAS  Article  Google Scholar 

  44. 44.

    Stork CT, Bocek M, Crossley MP, Sollier J, Sanz LA, Chedin F, et al. Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage. Elife. 2016;5. https://doi.org/10.7554/eLife.17548.

  45. 45.

    Majhi PD, Sharma, A, Roberts AL, Daniele E, Majewski AR, Chuong LM, Black AL, Vandenberg LN, Schneider SS, Dunphy KA, Jerry DJ. Effects of benzophenone-3 and propylparaben on estrorogen-receptor-dependent R-loops and DNA damage in breast epithelial cells and mice. Environ Health Perspect. 2020;128(1):17002. https://doi.org/10.1289/EHP5221.

  46. 46.

    Ciarloni L, Mallepell S, Brisken C. Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development. Proc Natl Acad Sci U S A. 2007;104(13):5455–60. https://doi.org/10.1073/pnas.0611647104.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Peterson EA, Jenkins EC, Lofgren KA, Chandiramani N, Liu H, Aranda E, et al. Amphiregulin is a critical downstream effector of estrogen signaling in ERalpha-positive breast Cancer. Cancer Res. 2015;75(22):4830–8. https://doi.org/10.1158/0008-5472.Can-15-0709.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Putnik M, Zhao C, Gustafsson JA, Dahlman-Wright K. Global identification of genes regulated by estrogen signaling and demethylation in MCF-7 breast cancer cells. Biochem Biophys Res Commun. 2012;426(1):26–32. https://doi.org/10.1016/j.bbrc.2012.08.007.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Laidlaw IJ, Clarke RB, Howell A, Owen AW, Potten CS, Anderson E. The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology. 1995;136(1):164–71. https://doi.org/10.1210/endo.136.1.7828527.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    McManus MJ, Welsch CW. The effect of estrogen, progesterone, thyroxine, and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice. Cancer. 1984;54(9):1920–7. https://doi.org/10.1002/1097-0142(19841101)54:9<1920::aid-cncr2820540924>3.0.co;2-f.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Becker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, et al. Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways. Oncogene. 2005;24(42):6345–53. https://doi.org/10.1038/sj.onc.1208787.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Rotunno M, Sun X, Figueroa J, Sherman ME, Garcia-Closas M, Meltzer P, et al. Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status. Breast Cancer Res. 2014;16(4):R74. https://doi.org/10.1186/bcr3689.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sun X, Casbas-Hernandez P, Bigelow C, Makowski L, Joseph Jerry D, Smith Schneider S, et al. Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat. 2012;131(3):1003–12. https://doi.org/10.1007/s10549-011-1789-3.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Troester MA, Lee MH, Carter M, Fan C, Cowan DW, Perez ER, et al. Activation of host wound responses in breast cancer microenvironment. Clin Cancer Res. 2009;15(22):7020–8. https://doi.org/10.1158/1078-0432.Ccr-09-1126.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Sturgeon SR, Arcaro KF, Johnson MA, Balasubramanian R, Zorn M, Jerry DJ, et al. DNA methylation in paired breast epithelial and white blood cells from women undergoing reduction mammoplasty. Anticancer Res. 2014;34(6):2985–90.

    CAS  PubMed  Google Scholar 

  56. 56.

    Browne EP, Punska EC, Lenington S, Otis CN, Anderton DL, Arcaro KF. Increased promoter methylation in exfoliated breast epithelial cells in women with a previous breast biopsy. Epigenetics. 2011;6(12):1425–35. https://doi.org/10.4161/epi.6.12.18280.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Zhao C, Lam EW, Sunters A, Enmark E, De Bella MT, Coombes RC, et al. Expression of estrogen receptor beta isoforms in normal breast epithelial cells and breast cancer: regulation by methylation. Oncogene. 2003;22(48):7600–6. https://doi.org/10.1038/sj.onc.1207100.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Al-Ghnaniem R, Peters J, Foresti R, Heaton N, Pufulete M. Methylation of estrogen receptor alpha and mutL homolog 1 in normal colonic mucosa: association with folate and vitamin B-12 status in subjects with and without colorectal neoplasia. Am J Clin Nutr. 2007;86(4):1064–72. https://doi.org/10.1093/ajcn/86.4.1064.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Schneider CA, Rasband WS, Eliceiri KW. NIH image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5.

    CAS  Article  Google Scholar 

  60. 60.

    Russo J, Rivera R, Russo IH. Influence of age and parity on the development of the human breast. Breast Cancer Res Treat. 1992;23(3):211–8.

    CAS  Article  Google Scholar 

  61. 61.

    Chang EC, Frasor J, Komm B, Katzenellenbogen BS. Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology. 2006;147(10):4831–42. https://doi.org/10.1210/en.2006-0563.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Brooks JD, Sung JS, Pike MC, Orlow I, Stanczyk FZ, Bernstein JL, et al. MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women. Int J Cancer. 2018;143(4):823–30. https://doi.org/10.1002/ijc.31370.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Conway K, Parrish E, Edmiston SN, Tolbert D, Tse CK, Moorman P, et al. Risk factors for breast cancer characterized by the estrogen receptor alpha A908G (K303R) mutation. Breast Cancer Res. 2007;9(3):R36–10. https://doi.org/10.1186/bcr1731.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20(7):1757–67. https://doi.org/10.1158/1078-0432.Ccr-13-2332.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Conway K, Parrish E, Edmiston SN, Tolbert D, Tse CK, Geradts J, et al. The estrogen receptor-alpha A908G (K303R) mutation occurs at a low frequency in invasive breast tumors: results from a population-based study. Breast Cancer Res. 2005;7(6):R871–80. https://doi.org/10.1186/bcr1315.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Abbasi S, Rasouli M, Nouri M, Kalbasi S. Association of estrogen receptor-alpha A908G (K303R) mutation with breast cancer risk. Int J Clin Exp Med. 2013;6(1):39–49.

    CAS  PubMed  Google Scholar 

  67. 67.

    Herynk MH, Parra I, Cui Y, Beyer A, Wu MF, Hilsenbeck SG, et al. Association between the estrogen receptor alpha A908G mutation and outcomes in invasive breast cancer. Clin Cancer Res. 2007;13(11):3235–43. https://doi.org/10.1158/1078-0432.Ccr-06-2608.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Schubert EL, Lee MK, Newman B, King MC. Single nucleotide polymorphisms (SNPs) in the estrogen receptor gene and breast cancer susceptibility. J Steroid Biochem Mol Biol. 1999;71(1–2):21–7. https://doi.org/10.1016/s0960-0760(99)00126-0.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Gabrielson M, Chiesa F, Paulsson J, Strell C, Behmer C, Ronnow K, et al. Amount of stroma is associated with mammographic density and stromal expression of oestrogen receptor in normal breast tissues. Breast Cancer Res Treat. 2016;158(2):253–61. https://doi.org/10.1007/s10549-016-3877-x.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Chamberlin T, D'Amato JV, Arendt LM. Obesity reversibly depletes the basal cell population and enhances mammary epithelial cell estrogen receptor alpha expression and progenitor activity. Breast Cancer Res. 2017;19(1):128. https://doi.org/10.1186/s13058-017-0921-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Goyal R, Gupta T, Gupta R, Aggarwal A, Sahni D, Singh G. Histological and immunohistochemical study of estrogen and progesterone receptors in normal human breast tissue in adult age groups vulnerable to malignancy. Clin Anat. 2016;29(6):729–37. https://doi.org/10.1002/ca.22723.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Quong J, Eppenberger-Castori S, Moore D 3rd, Scott GK, Birrer MJ, Kueng W, et al. Age-dependent changes in breast cancer hormone receptors and oxidant stress markers. Breast Cancer Res Treat. 2002;76(3):221–36.

    CAS  Article  Google Scholar 

  73. 73.

    Oh H, Eliassen AH, Wang M, Smith-Warner SA, Beck AH, Schnitt SJ, et al. Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer. NPJ Breast Cancer. 2016;2:1–3. https://doi.org/10.1038/npjbcancer.2016.32.

    Article  Google Scholar 

  74. 74.

    Gabrielson M, Chiesa F, Behmer C, Ronnow K, Czene K, Hall P. Association of reproductive history with breast tissue characteristics and receptor status in the normal breast. Breast Cancer Res Treat. 2018;170(3):487–97. https://doi.org/10.1007/s10549-018-4768-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Asztalos S, Gann PH, Hayes MK, Nonn L, Beam CA, Dai Y, et al. Gene expression patterns in the human breast after pregnancy. Cancer Prev Res (Phila). 2010;3(3):301–11. https://doi.org/10.1158/1940-6207.Capr-09-0069.

    CAS  Article  Google Scholar 

  76. 76.

    Pink JJ, Jordan VC. Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res. 1996;56(10):2321–30.

    CAS  PubMed  Google Scholar 

  77. 77.

    Read LD, Greene GL, Katzenellenbogen BS. Regulation of estrogen receptor messenger ribonucleic acid and protein levels in human breast cancer cell lines by sex steroid hormones, their antagonists, and growth factors. Mol Endocrinol. 1989;3(2):295–304. https://doi.org/10.1210/mend-3-2-295.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Saceda M, Lippman ME, Chambon P, Lindsey RL, Ponglikitmongkol M, Puente M, et al. Regulation of the estrogen receptor in MCF-7 cells by estradiol. Mol Endocrinol. 1988;2(12):1157–62. https://doi.org/10.1210/mend-2-12-1157.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Eckert RL, Mullick A, Rorke EA, Katzenellenbogen BS. Estrogen receptor synthesis and turnover in MCF-7 breast cancer cells measured by a density shift technique. Endocrinology. 1984;114(2):629–37. https://doi.org/10.1210/endo-114-2-629.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Berkenstam A, Glaumann H, Martin M, Gustafsson JA, Norstedt G. Hormonal regulation of estrogen receptor messenger ribonucleic acid in T47Dco and MCF-7 breast cancer cells. Mol Endocrinol. 1989;3(1):22–8. https://doi.org/10.1210/mend-3-1-22.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Sotoca AM, van den Berg H, Vervoort J, van der Saag P, Strom A, Gustafsson JA, et al. Influence of cellular ERalpha/ERbeta ratio on the ERalpha-agonist induced proliferation of human T47D breast cancer cells. Toxicol Sci. 2008;105(2):303–11. https://doi.org/10.1093/toxsci/kfn141.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Hodges-Gallagher L, Valentine CD, El Bader S, Kushner PJ. Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells. Breast Cancer Res Treat. 2008;109(2):241–50. https://doi.org/10.1007/s10549-007-9640-6.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Paruthiyil S, Cvoro A, Tagliaferri M, Cohen I, Shtivelman E, Leitman DC. Estrogen receptor beta causes a G2 cell cycle arrest by inhibiting CDK1 activity through the regulation of cyclin B1, GADD45A, and BTG2. Breast Cancer Res Treat. 2011;129(3):777–84. https://doi.org/10.1007/s10549-010-1273-5.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Meng P, Vaapil M, Tagmount A, Loguinov A, Vulpe C, Yaswen P. Propagation of functional estrogen receptor positive normal human breast cells in 3D cultures. Breast Cancer Res Treat. 2019;176(1):131–40. https://doi.org/10.1007/s10549-019-05229-5.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Haynes BP, Viale G, Galimberti V, Rotmensz N, Gibelli B, Smith IE, et al. Differences in expression of proliferation-associated genes and RANKL across the menstrual cycle in estrogen receptor-positive primary breast cancer. Breast Cancer Res Treat. 2014;148(2):327–35. https://doi.org/10.1007/s10549-014-3181-6.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Lanng MB, Moller CB, Andersen AH, Palsdottir AA, Roge R, Ostergaard LR, et al. Quality assessment of Ki67 staining using cell line proliferation index and stain intensity features. Cytometry A. 2019;95(4):381–8. https://doi.org/10.1002/cyto.a.23683.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Polley MY, Leung SC, Gao D, Mastropasqua MG, Zabaglo LA, Bartlett JM, et al. An international study to increase concordance in Ki67 scoring. Mod Pathol. 2015;28(6):778–86. https://doi.org/10.1038/modpathol.2015.38.

    Article  PubMed  Google Scholar 

  88. 88.

    Mengel M, von Wasielewski R, Wiese B, Rudiger T, Muller-Hermelink HK, Kreipe H. Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-Centre trial. J Pathol. 2002;198(3):292–9. https://doi.org/10.1002/path.1218.

    Article  PubMed  Google Scholar 

  89. 89.

    Jurikova M, Danihel L, Polak S, Varga I. Ki67, PCNA, and MCM proteins: markers of proliferation in the diagnosis of breast cancer. Acta Histochem. 2016;118(5):544–52. https://doi.org/10.1016/j.acthis.2016.05.002.

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Qiu X, Wang H, Wang Z, Fu Y, Yin J. Expression of PCNA, Ki-67 and COX-2 in breast cancer based on DCE-MRI image information. J Infect Public Health. 2019. https://doi.org/10.1016/j.jiph.2019.06.024.

  91. 91.

    Potten CS, Watson RJ, Williams GT, Tickle S, Roberts SA, Harris M, et al. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer. 1988;58(2):163–70. https://doi.org/10.1038/bjc.1988.185.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Ramakrishnan R, Khan SA, Badve S. Morphological changes in breast tissue with menstrual cycle. Mod Pathol. 2002;15(12):1348–56. https://doi.org/10.1097/01.Mp.0000039566.20817.46.

    Article  PubMed  Google Scholar 

  93. 93.

    Navarrete MA, Maier CM, Falzoni R, Quadros LG, Lima GR, Baracat EC, et al. Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle. Breast Cancer Res. 2005;7(3):R306–13. https://doi.org/10.1186/bcr994.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354(3):270–82. https://doi.org/10.1056/NEJMra050776.

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Roy D, Liehr JG. Estrogen, DNA damage and mutations. Mutat Res. 1999;424(1–2):107–15. https://doi.org/10.1016/s0027-5107(99)00012-3.

    CAS  Article  PubMed  Google Scholar 

  96. 96.

    Santen R, Cavalieri E, Rogan E, Russo J, Guttenplan J, Ingle J, et al. Estrogen mediation of breast tumor formation involves estrogen receptor-dependent, as well as independent, genotoxic effects. Ann N Y Acad Sci. 2009;1155:132–40. https://doi.org/10.1111/j.1749-6632.2008.03685.x.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

Research reported in this publication was supported, in part, by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number U01ES026140 (DJJ, SSS) and R01ES015739 (DJJ). Funding was also provided by the Department of Defense under contract #W81XWH-15-1-0217 (DJJ) and the Rays of Hope Center for Breast Cancer Research (KAD, GMJ, DJJ).

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Dunphy, K.A., Black, A.L., Roberts, A.L. et al. Inter-Individual Variation in Response to Estrogen in Human Breast Explants. J Mammary Gland Biol Neoplasia 25, 51–68 (2020). https://doi.org/10.1007/s10911-020-09446-3

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Keywords

  • Human breast explants
  • Estrogen receptor
  • Estrogen signaling