Skip to main content

Advertisement

Log in

Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1

Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The study was conducted to determine the effect of physical activity on DNA methylation and to predict the consequence of this effect concerning gene expression and breast cancer survival. Blood samples, collected from 12 breast cancer patients who participated in a randomized clinical trial of exercise, were examined for exercise-related changes in DNA methylation using a methylation microarray. Tumor samples of 348 breast cancer patients were analyzed with qRT-PCR and qMSP to determine gene expression and methylation identified in the microarray analysis. Cox regression models were developed to predict survival outcomes in association with gene expression and methylation. After 6 months of moderate-intensity aerobic exercise, changes in DNA methylation (P < 5 × 10−5) in peripheral blood leukocytes were detected in 43 genes from a panel of 14 495. Based on the list, we analyzed gene expression in association with overall survival in breast tumors and found three genes whose methylation was reduced after exercise were favorably in association with overall survival, i.e., higher expression associated with better survival. Of the three genes, L3MBTL1 was a putative tumor suppressor gene with known function to repress chromatin for transcription, which is activated mainly in germline stem cells. Further analyses of tumor features among patients indicated that high expression of L3MBTL1 was associated with low grade and hormone receptor–positive tumors, as well as low risk of disease recurrence and breast cancer death. In conclusion, the study suggests that increasing physical activity after a breast cancer diagnosis may affect epigenetic regulation of tumor suppressor genes, which have favorable impacts on survival outcomes of breast cancer patients.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Holick CN, Newcomb PA, Trentham-Dietz A, Titus-Ernstoff L, Bersch AJ, Stampfer MJ, Baron JA, Egan KM, Willett WC (2008) Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomarkers Prev 17(2):379–386

    Article  PubMed  Google Scholar 

  2. Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA (2005) Physical activity and survival after breast cancer diagnosis. JAMA 293(20):2479–2486

    Article  PubMed  CAS  Google Scholar 

  3. Irwin ML, Smith AW, McTiernan A, Ballard-Barbash R, Cronin K, Gilliland FD, Baumgartner RN, Baumgartner KB, Bernstein L (2008) Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 26(24):3958–3964

    Article  PubMed  Google Scholar 

  4. McTiernan A, Tworoger SS, Rajan KB, Yasui Y, Sorenson B, Ulrich CM, Chubak J, Stanczyk FZ, Bowen D, Irwin ML et al (2004) Effect of exercise on serum androgens in postmenopausal women: a 12-month randomized clinical trial. Cancer Epidemiol Biomarkers Prev 13(7):1099–1105

    PubMed  CAS  Google Scholar 

  5. McTiernan A, Tworoger SS, Ulrich CM, Yasui Y, Irwin ML, Rajan KB, Sorensen B, Rudolph RE, Bowen D, Stanczyk FZ et al (2004) Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized clinical trial. Cancer Res 64(8):2923–2928

    Article  PubMed  CAS  Google Scholar 

  6. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y, Hartwick W, Hoffman B, Hood N (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20(1):42–51

    Article  PubMed  CAS  Google Scholar 

  7. Neilson HK, Friedenreich CM, Brockton NT, Millikan RC (2009) Physical activity and postmenopausal breast cancer: proposed biologic mechanisms and areas for future research. Cancer Epidemiol Biomarkers Prev 18(1):11–27

    Article  PubMed  CAS  Google Scholar 

  8. Ligibel JA, Campbell N, Partridge A, Chen WY, Salinardi T, Chen H, Adloff K, Keshaviah A, Winer EP (2008) Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26(6):907–912

    Article  PubMed  CAS  Google Scholar 

  9. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Hartwick W, Hoffma B, Hood N (2002) Insulin-like growth factor binding proteins 1 and 3 and breast cancer outcomes. Breast Cancer Res Treat 74(1):65–76

    Article  PubMed  CAS  Google Scholar 

  10. Irwin ML, Varma K, Alvarez-Reeves M, Cadmus L, Wiley A, Chung GG, Dipietro L, Mayne ST, Yu H (2009) Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study. Cancer Epidemiol Biomarkers Prev 18(1):306–313

    Article  PubMed  CAS  Google Scholar 

  11. Schmitz KH, Ahmed RL, Hannan PJ, Yee D (2005) Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins. Cancer Epidemiol Biomarkers Prev 14(7):1672–1680

    Article  PubMed  CAS  Google Scholar 

  12. Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR (2003) Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Cancer Epidemiol Biomarkers Prev 12(8):721–727

    PubMed  CAS  Google Scholar 

  13. Coyle YM, Xie XJ, Lewis CM, Bu D, Milchgrub S, Euhus DM (2007) Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue. Cancer Epidemiol Biomarkers Prev 16(2):192–196

    Article  PubMed  CAS  Google Scholar 

  14. Yuasa Y, Nagasaki H, Akiyama Y, Hashimoto Y, Takizawa T, Kojima K, Kawano T, Sugihara K, Imai K, Nakachi K (2009) DNA methylation status is inversely correlated with green tea intake and physical activity in gastric cancer patients. Int J Cancer 124(11):2677–2682

    Article  PubMed  CAS  Google Scholar 

  15. Irwin ML, Cadmus L, Alvarez-Reeves M, O’Neil M, Mierzejewski E, Latka R, Yu H, Dipietro L, Jones B, Knobf MT et al (2008) Recruiting and retaining breast cancer survivors into a randomized controlled exercise trial: the Yale Exercise and Survivorship Study. Cancer 112(11 Suppl):2593–2606

    Article  PubMed  Google Scholar 

  16. Mu L, Katsaros D, Lu L, Preti M, Durando A, Arisio R, Yu H (2008) TGF-beta1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival. Br J Cancer 99(8):1357–1363

    Article  PubMed  CAS  Google Scholar 

  17. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O’Brien WL, Bassett DR Jr, Schmitz KH, Emplaincourt PO et al (2000) Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 32(9 Suppl):S498–S504

    PubMed  CAS  Google Scholar 

  18. Lu L, Katsaros D, de la Longrais IA, Sochirca O, Yu H (2007) Hypermethylation of let-7a–3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. Cancer Res 67(21):10117–10122

    Article  PubMed  CAS  Google Scholar 

  19. Plaitakis A, Zaganas I (2001) Regulation of human glutamate dehydrogenases: implications for glutamate, ammonia and energy metabolism in brain. J Neurosci Res 66(5):899–908

    Article  PubMed  CAS  Google Scholar 

  20. Bonasio R, Lecona E, Reinberg D (2010) MBT domain proteins in development and disease. Semin Cell Dev Biol 21(2):221–223

    Article  PubMed  CAS  Google Scholar 

  21. Satoh K, Ginsburg E, Vonderhaar BK (2004) Msx-1 and Msx-2 in mammary gland development. J Mammary Gland Biol Neoplasia 9(2):195–205

    Article  PubMed  Google Scholar 

  22. Nakajima K, Takeoka M, Mori M, Hashimoto S, Sakurai A, Nose H, Higuchi K, Itano N, Shiohara M, Oh T et al (2010) Exercise effects on methylation of ASC gene. Int J Sports Med 31(9):671–675

    Article  PubMed  CAS  Google Scholar 

  23. DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9(4):212

    Article  PubMed  Google Scholar 

  24. Allavena P, Sica A, Solinas G, Porta C, Mantovani A (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66(1):1–9

    Article  PubMed  Google Scholar 

  25. Boccuni P, MacGrogan D, Scandura JM, Nimer SD (2003) The human L(3)MBT polycomb group protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6). J Biol Chem 278(17):15412–15420

    Article  PubMed  CAS  Google Scholar 

  26. Bench AJ, Li J, Huntly BJ, Delabesse E, Fourouclas N, Hunt AR, Deloukas P, Green AR (2004) Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies. Br J Haematol 127(5):509–518

    Article  PubMed  CAS  Google Scholar 

  27. Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S, Mack S, Kongkham PN, Peacock J, Dubuc A et al (2009) Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet 41(4):465–472

    Article  PubMed  CAS  Google Scholar 

  28. Addou-Klouche L, Adelaide J, Finetti P, Cervera N, Ferrari A, Bekhouche I, Sircoulomb F, Sotiriou C, Viens P, Moulessehoul S et al (2010) Loss, mutation and deregulation of L3MBTL4 in breast cancers. Mol Cancer 9:213

    Article  PubMed  Google Scholar 

  29. Janic A, Mendizabal L, Llamazares S, Rossell D, Gonzalez C (2010) Ectopic expression of germline genes drives malignant brain tumor growth in Drosophila. Science 330(6012):1824–1827

    Article  PubMed  CAS  Google Scholar 

  30. Buehlmeyer K, Doering F, Daniel H, Kindermann B, Schulz T, Michna H (2008) Alteration of gene expression in rat colon mucosa after exercise. Ann Anat 190(1):71–80

    Article  PubMed  CAS  Google Scholar 

  31. Luster AD, Jhanwar SC, Chaganti RS, Kersey JH, Ravetch JV (1987) Interferon-inducible gene maps to a chromosomal band associated with a (4;11) translocation in acute leukemia cells. Proc Natl Acad Sci USA 84(9):2868–2871

    Article  PubMed  CAS  Google Scholar 

  32. O’Donovan N, Galvin M, Morgan JG (1999) Physical mapping of the CXC chemokine locus on human chromosome 4. Cytogenet Cell Genet 84(1–2):39–42

    Article  PubMed  Google Scholar 

  33. Ueda K, Clark DP, Chen CJ, Roninson IB, Gottesman MM, Pastan I (1987) The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. J Biol Chem 262(2):505–508

    PubMed  CAS  Google Scholar 

  34. Wong WT, Kraus MH, Carlomagno F, Zelano A, Druck T, Croce CM, Huebner K, Di Fiore PP (1994) The human eps15 gene, encoding a tyrosine kinase substrate, is conserved in evolution and maps to 1p31–p32. Oncogene 9(6):1591–1597

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Herbert Yu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zeng, H., Irwin, M.L., Lu, L. et al. Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1 . Breast Cancer Res Treat 133, 127–135 (2012). https://doi.org/10.1007/s10549-011-1716-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1716-7

Keywords

Navigation