Breast Cancer Research and Treatment

, Volume 162, Issue 1, pp 115–125 | Cite as

Associations of obesity and physical activity with serum and intratumoral sex steroid hormone levels among postmenopausal women with breast cancer: analysis of paired serum and tumor tissue samples

  • Yoichiro Kakugawa
  • Hiroshi Tada
  • Masaaki Kawai
  • Takashi Suzuki
  • Yoshikazu Nishino
  • Seiki Kanemura
  • Takanori Ishida
  • Noriaki Ohuchi
  • Yuko Minami



It has been hypothesized that intratumoral estrogens may play important roles in the growth of breast cancer. However, few studies have investigated such intratumoral hormones, or their association with risk factors of breast cancer.


In this cross-sectional study, hormone levels in paired serum and tumor tissue samples from 146 postmenopausal women with breast cancer were measured by liquid chromatography-tandem mass spectrometry and compared between estrogen/progesterone (ER/PgR) subtypes. The associations of risk factors including body mass index (BMI) and other lifestyle factors with these hormone levels were investigated using analysis of covariance.


The level of estradiol (E2) in tumor tissue was extremely high in women with ER+ (geometric mean 95.6 pg/g) relative to women with ER−/PgR− (8.9 pg/g), whereas serum E2 level did not differ much between the two groups (3.1 and 2.8 pg/ml, respectively). Serum levels of precursors for E2, including testosterone (T) and androstenedione (Adione), and tissue Adione level, were high among women with ER+. After adjustment for confounding variables, BMI was found to be positively associated with tissue levels of E2, estrone (E1), T, and Adione among women with ER+ (P trend < 0.0001 for E2; 0.0016 for E1; 0.0002 for T; and 0.03 for Adione).


The data suggest that tissue E2 is related to the growth of receptor-positive breast cancer and that risk factors such as BMI affect tissue levels of E2 and its precursors. Understanding of hormonal environments within tumor tissue may be important for elucidating hormonal etiology of breast cancer and improving the prognosis of patients.


Breast cancer Hormone receptor Estradiol Serum Tumor tissue BMI 



This work was supported by the Grants-in-Aid from the Japan Society for the Promotion of Science (B) (23390169).

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Supplementary material

10549_2016_4094_MOESM1_ESM.xlsx (24 kb)
Supplementary material 1 (XLSX 24 kb)


  1. 1.
    Hori M, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H, Japan Cancer Surveillance Research Group (2015) Cancer incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Jpn J Clin Oncol 45: 884–891Google Scholar
  2. 2.
    Ito Y, Miyashiro I, Ito H, Hosono S, Chihara D, Nakata-Yamada K, Nakayama M, Matsuzaka M, Hattori M, Sugiyama H, Oze I, Tanaka R, Nomura E, Nishino Y, Matsuda T, Ioka A, Tsukuma H, Nakayama T, J-CANSIS Research Group (2014) Long-term survival and conditional survival of cancer patients in Japan using population-based cancer registry data. Cancer Sci 105: 1480–1486Google Scholar
  3. 3.
    Kushi LH, Kwan ML, Lee MM, Ambrosone CB (2007) Lifestyle factors and survival in women with breast cancer. J Nutr 137:236S–242SPubMedGoogle Scholar
  4. 4.
    Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, Bandera EV, Hamilton KK, Grant B, McCullough M, Byers T, Gansler T (2012) Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin 62:243–274CrossRefPubMedGoogle Scholar
  5. 5.
    Kawai M, Minami Y, Nishino Y, Fukamachi K, Ohuchi N, Kakugawa Y (2012) Body mass index and survival after breast cancer diagnosis in Japanese women. BMC Cancer 12:149CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, Longcope C, Speizer FE (1995) Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 87:1297–1302CrossRefPubMedGoogle Scholar
  7. 7.
    Nagata C, Kabuto M, Takatsuka N, Shimizu H (1997) Associations of alcohol, height, and reproductive factors with serum hormone concentrations in postmenopausal women. Steroid hormones in Japanese postmenopausal women. Breast Cancer Res Treat 44:235–241CrossRefPubMedGoogle Scholar
  8. 8.
    McTiernan A, Wu L, Chen C, Chlebowski R, Mossavar-Rahmani Y, Modugno F, Perri MG, Stanczyk FZ, Van Horn L, Wang CY, Investigators Women’s Health Initiative (2006) Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity 14:1662–1677CrossRefPubMedGoogle Scholar
  9. 9.
    Endogenous Hormones and Breast Cancer Collaborative Group (2011) Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 105:709–722CrossRefGoogle Scholar
  10. 10.
    Miller WR, Hawkins RA, Forrest AP (1982) Significance of aromatase activity in human breast cancer. Cancer Res 42:3365s–3368sPubMedGoogle Scholar
  11. 11.
    Honma N, Saji S, Hirose M, Horiguchi S, Kuroi K, Hayashi S, Utsumi T, Harada N (2011) Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3β, 17β-diol. Cancer Sci 102:1848–1854CrossRefPubMedGoogle Scholar
  12. 12.
    Lønning PE, Helle H, Duong NK, Ekse D, Aas T, Geisler J (2009) Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status. J Steroid Biochem Mol Biol 117:31–41CrossRefPubMedGoogle Scholar
  13. 13.
    van Landeghem AA, Poortman J, Nabuurs M, Thijssen JH (1985) Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res 45:2900–2906PubMedGoogle Scholar
  14. 14.
    Pasqualini JR, Chetrite G, Blacker C, Feinstein MC, Delalonde L, Talbi M, Maloche C (1996) Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. J Clin Endocrinol Metab 81:1460–1464PubMedGoogle Scholar
  15. 15.
    Yaghjyan L, Colditz GA (2011) Estrogens in the breast tissue: a systematic review. Cancer Causes Control 22:529–540CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90:1292–1299CrossRefPubMedGoogle Scholar
  17. 17.
    Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME (2004) Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomarkers Prev 13:1558–1568PubMedGoogle Scholar
  18. 18.
    McNamara KM, Sasano H (2015) The intracrinology of breast cancer. J Steroid Biochem Mol Biol 145:172–178CrossRefPubMedGoogle Scholar
  19. 19.
    Pfeiler G, Treeck O, Wenzel G, Goerse R, Hartmann A, Schmitz G, Ortmann (2009) Correlation of body mass index and menopausal status with the intra-tumoral estrogen system in invasive breast cancer. Gynecol Endocrinol 25:183–187CrossRefPubMedGoogle Scholar
  20. 20.
    Kawai M, Kakugawa Y, Nishino Y, Hamanaka Y, Ohuchi N, Minami Y (2012) Reproductive factors and breast cancer risk in relation to hormone receptor and menopausal status in Japanese women. Cancer Sci 103:1861–1870CrossRefPubMedGoogle Scholar
  21. 21.
    Kakugawa Y, Kawai M, Nishino Y, Fukamachi K, Ishida T, Ohuchi N, Minami Y (2015) Smoking and survival after breast cancer diagnosis in Japanese women: a prospective cohort study. Cancer Sci 106:1066–1074CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nelson RE, Grebe SK, OKane DJ, Singh RJ (2004) Liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of estradiol and estrone in human plasma. Clin Chem 50:373–384CrossRefPubMedGoogle Scholar
  23. 23.
    Stanczyk FZ, Mathews BW, Sherman ME (2015) Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: a critical appraisal of current science. Steroids 99:91–102CrossRefPubMedGoogle Scholar
  24. 24.
    Haynes BP, Straume AH, Geisler J, A’Hern R, Helle H, Smith IE, Lønning PE, Dowsett M (2010) Intratumoral estrogen disposition in breast cancer. Clin Cancer Res 16:1790–1801CrossRefPubMedGoogle Scholar
  25. 25.
    Russo J, Russo IH (2006) The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol 102:89–96CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kabuto M, Akiba S, Stevens RG, Neriishi K, Land CE (2000) A prospective study of estradiol and breast cancer in Japanese women. Cancer Epidemiol Biomarkers Prev 9:575–579PubMedGoogle Scholar
  27. 27.
    Key T, Appleby P, Barnes I, Reeves G, Endogenous Hormones and Breast Cancer Collaborative Group (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94: 606–616Google Scholar
  28. 28.
    Baglietto L, Severi G, English DR, Krishnan K, Hopper JL, McLean C, Morris HA, Tilley WD, Giles GG (2010) Circulating steroid hormone levels and risk of breast cancer for postmenopausal women. Cancer Epidemiol Biomarkers Prev 19:492–502CrossRefPubMedGoogle Scholar
  29. 29.
    Zeleniuch-Jacquotte A, Toniolo P, Levitz M, Shore RE, Koenig KL, Banerjee S, Strax P, Pasternack BS (1995) Endogenous estrogens and risk of breast cancer by estrogen receptor status: a prospective study in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 4:857–860PubMedGoogle Scholar
  30. 30.
    Farhat GN, Cummings SR, Chlebowski RT, Parimi N, Cauley JA, Rohan TE, Huang AJ, Vitolins M, Hubbell FA, Manson JE, Cochrane BB, Lane DS, Lee JS (2011) Sex hormone levels and risks of estrogen receptor-negative and estrogen receptor-positive breast cancers. J Natl Cancer Inst 103:562–570CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Siiteri PK (1987) Adipose tissue as a source of hormones. Am J Clin Nutr 45 (1 Supple): 277–282Google Scholar
  32. 32.
    Lønning PE, Dowsett M, Powles TJ (1990) Postmenopausal estrogen synthesis and metabolism: alterations caused by aromatase inhibitors used for the treatment of breast cancer. J Steroid Biochem 35:355–366CrossRefPubMedGoogle Scholar
  33. 33.
    Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A’hern R, Crowder RJ, Hoog J, Smith IE, Osin P, Nerurkar A, Parker JS, Perou CM, Ellis MJ, Dowsett M (2010) Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J Clin Oncol 28:1161–1167CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lønning PE, Haynes BP, Straume AH, Dunbier A, Helle H, Knappskog S, Dowsett M (2011) Exploring breast cancer estrogen disposition: the basis for endocrine manipulation. Clin Cancer Res 17:4948–4958CrossRefPubMedGoogle Scholar
  35. 35.
    Falk RT, Gentzschein E, Stanczyk FZ, Garcia-Closas M, Figueroa JD, Ioffe OB, Lissowska J, Brinton LA, Sherman ME (2012) Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women. Breast Cancer Res Treat 131:287–294CrossRefPubMedGoogle Scholar
  36. 36.
    Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER (1993) A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 77:1622–1628PubMedGoogle Scholar
  37. 37.
    Reed MJ, Purohit A (2001) Aromatase regulation and breast cancer. Clin Endocrinol 54:563–571CrossRefGoogle Scholar
  38. 38.
    Gruber CJ, Tschugguel W, Schneeberger C, Huber JC (2002) Production and actions of estrogens. N Engl J Med 346:340–352CrossRefPubMedGoogle Scholar
  39. 39.
    Suzuki T, Miki Y, Moriya T, Akahira J, Hirakawa H, Ohuchi N, Sasano H (2007) In situ production of sex steroids in human breast carcinoma. Med Mol Morphol 40:121–127CrossRefPubMedGoogle Scholar
  40. 40.
    Tinwell H, Rascle JB, Colombel S, Al Khansa I, Freyberger A, Bars R (2011) A novel method for measuring aromatase activity in tissue samples by determining estradiol concentrations. J Appl Toxicol 31:446–454CrossRefPubMedGoogle Scholar
  41. 41.
    Chetrite GS, Cortes-Prieto J, Philippe JC, Wright F, Pasqualini JR (2000) Comparison of estrogen concentrations, estrone sulfatase and aromatase activities in normal, and in cancerous, human breast tissues. J Steroid Biochem Mol Biol 72:23–27CrossRefPubMedGoogle Scholar
  42. 42.
    Miki Y, Suzuki T, Tazawa C, Yamaguchi Y, Kitada K, Honma S, Moriya T, Hirakawa H, Evans DB, Hayashi S, Ohuchi N, Sasano H (2007) Aromatase localization in human breast cancer tissues: possible interactions between intratumoral stromal and parenchymal cells. Cancer Res 67:3945–3954CrossRefPubMedGoogle Scholar
  43. 43.
    Bulun SE, Chen D, Moy I, Brooks DC, Zhao H (2012) Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 23:83–89CrossRefPubMedGoogle Scholar
  44. 44.
    Hanamura T, Niwa T, Gohno T, Kurosumi M, Takei H, Yamaguchi Y, Ito K, Hayashi S (2014) Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers. Breast Cancer Res Treat 143:69–80CrossRefPubMedGoogle Scholar
  45. 45.
    McTiernan A, Rajan KB, Tworoger SS, Irwin M, Bernstein L, Baumgartner R, Gilliland F, Stanczyk FZ, Yasui Y, Ballard-Barbash R (2003) Adiposity and sex hormones in postmenopausal breast cancer survivors. J Clin Oncol 21:1961–1966CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rock CL, Flatt SW, Laughlin GA, Gold EB, Thomson CA, Natarajan L, Jones LA, Caan BJ, Stefanick ML, Hajek RA, Al-Delaimy WK, Stanczyk FZ, Pierce JP, Women’s Healthy Eating and Living Study Group (2008) Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomarkers Prev 17:614–620Google Scholar
  47. 47.
    Duggan C, Stanczyk F, Campbell K, Neuhouser ML, Baumgartner RN, Baumgartner KB, Bernstein L, Ballard R, McTiernan A (2016) Associations of sex steroid hormones with mortality in women with breast cancer. Breast Cancer Res Treat 155:559–567CrossRefPubMedGoogle Scholar
  48. 48.
    Endogenous Hormones Breast Cancer Collaborative Group (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226CrossRefGoogle Scholar
  49. 49.
    Simpson ER, Mendelson CR (1987) Effect of aging and obesity on aromatase activity of human adipose cells. Am J Clin Nutr 45(1 Suppl):290–295PubMedGoogle Scholar
  50. 50.
    Bowers LW, Brenner AJ, Hursting SD, Tekmal RR, deGraffenried LA (2015) Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production. Breast Cancer Res Treat 149:49–57CrossRefPubMedGoogle Scholar
  51. 51.
    Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ (2013) Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res 19:6074–6083CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Chan MF, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Khaw KT (2007) Usual physical activity and endogenous sex hormones in postmenopausal women: the European prospective investigation into cancer-norfolk population study. Cancer Epidemiol Biomarkers Prev 16:900–905CrossRefPubMedGoogle Scholar
  53. 53.
    Bertone-Johnson ER, Tworoger SS, Hankinson SE (2009) Recreational physical activity and steroid hormone levels in postmenopausal women. Am J Epidemiol 170:1095–1104CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Suzuki R, Iwasaki M, Yamamoto S, Inoue M, Sasazuki S, Sawada N, Yamaji T, Shimazu T, Tsugane S, Japan Public Health Center-based Prospective Study Group (2011) Leisure-time physical activity and breast cancer risk defined by estrogen and progesterone receptor status–the Japan Public Health Center-based Prospective Study. Prev Med 52: 227–233Google Scholar
  55. 55.
    Wu Y, Zhang D, Kang S (2013) Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Res Treat 137:869–882CrossRefPubMedGoogle Scholar
  56. 56.
    Key TJ, Pike MC, Baron JA, Moore JW, Wang DY, Thomas BS, Bulbrook RD (1991) Cigarette smoking and steroid hormones in women. J Steroid Biochem Mol Biol 39:529–534CrossRefPubMedGoogle Scholar
  57. 57.
    Davies NJ, Batehup L, Thomas R (2011) The role of diet and physical activity in breast, colorectal, and prostate cancer survivorship: a review of the literature. Br J Cancer 105:S52–S73CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Chan DS, Vieira AR, Aune D, Bandera EV, Greenwood DC, McTiernan A, Navarro Rosenblatt D, Thune I, Vieira R, Norat T (2014) Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol 25:1901–1914CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ioannides SJ, Barlow PL, Elwood JM, Porter D (2014) Effect of obesity on aromatase inhibitor efficacy in postmenopausal, hormone receptor-positive breast cancer: a systematic review. Breast Cancer Res Treat 147:237–248CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yoichiro Kakugawa
    • 1
  • Hiroshi Tada
    • 2
  • Masaaki Kawai
    • 1
    • 2
    • 3
  • Takashi Suzuki
    • 4
  • Yoshikazu Nishino
    • 5
    • 6
  • Seiki Kanemura
    • 5
  • Takanori Ishida
    • 2
  • Noriaki Ohuchi
    • 2
  • Yuko Minami
    • 3
    • 5
    • 7
  1. 1.Department of Breast OncologyMiyagi Cancer Center HospitalNatoriJapan
  2. 2.Department of Surgical OncologyTohoku University Graduate School of MedicineSendaiJapan
  3. 3.Division of Community HealthTohoku University Graduate School of MedicineSendaiJapan
  4. 4.Division of Pathology and HistotechnologyTohoku University Graduate School of MedicineSendaiJapan
  5. 5.Division of Cancer Epidemiology and PreventionMiyagi Cancer Center Research InstituteNatoriJapan
  6. 6.Department of Epidemiology and Public HealthKanazawa Medical UniversityKahokuJapan
  7. 7.Center for Multiphasic Health CheckOsaki Citizen HospitalOsakiJapan

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