摘要
目的：通过制备4T1小鼠乳腺癌模型,施予不同强度的有氧运动、紫杉醇的单独或联合干预,研究运动及其与紫杉醇联合在乳腺癌治疗期的作用,并探讨其可能的机制,为丰富乳腺癌的治疗手段、扩大运动在乳腺癌防治中的应用范围提供实验依据。
方法：雌性BALB/c小鼠104只,按体重随机分为正常对照组(N)和模型组。模型组小鼠接种4T1细胞。建模成功后,按体重、瘤大小分为生理盐水组(C)、紫杉醇组(P)、运动1组(E1)、运动2组(E2)、联合1组(EP1)和联合2组(EP2)。P、EPl和EP2组腹腔注射紫杉醇,剂量20mg/kg/w,其它组注射等体积生理盐水。运动强度采用12和17米/分,每次30分钟,每周5次,共5周
结果：
1.4T1细胞接种在小鼠右腋皮下5天后,均有荷瘤生长,病理学检查为浸润性乳腺癌,造模成功。荷瘤组织ER、PR、Her-2的表达均为阴性。
2.接种瘤细胞后,小鼠体重下降。干预结束后,模型各组小鼠的体重均显著低于N组。运动、紫杉醇及联合干预均未能延缓荷瘤小鼠体重下降的情况,表现为从干预开始,模型各组间小鼠的体重均无显著差异。
3. P、EP1、EP2和E2组生存时间均延长。EP2组效果显著优于其它组。
4.EP2组瘤重、瘤体积、瘤体比显著低于C组。其它干预均未能明显延缓荷瘤增长。
5.模型各组小鼠淋巴结中调节性T细胞富集,显著高于N组。EP2组荷瘤、淋巴结中调节性T细胞富集现象明显改善。
6.EP2组荷瘤组织TGF-β1与IL-10表达显著下调。
7.EP2组S期比例显著降低、早、晚期凋亡比例显著增加。
8.EP2组NF-κ Bp65的表达显著下调。EP1、EP2与E2组P-IκBα蛋白的表达显著下调,且EP1、EP2的效果优于P,E2效果优于E1。
结论：
1.17米/分的中强度运动组小鼠生存时间延长,适度运动有助于荷瘤小鼠带瘤生存。
2.17米/分的中强度运动联合紫杉醇有效抑制了乳腺癌模型小鼠荷瘤的生长,运动、紫杉醇的单独干预效果不佳,17米/分的中强度运动可增强紫杉醇的治疗效果。
3.通过下调NF-κ Bp65、P-IκBα的表达,减少瘤细胞增殖,改善调节性T细胞在局部富集,削弱瘤细胞的免疫逃逸,促进其凋亡,可能是运动联合紫杉醇影响乳腺癌模型小鼠荷瘤生长的机制之一。
Purpose
The aim of this research is to study the effect of aerobic exercise of different intensity, paclitaxel and the combination of them in the treatment period of breast cancer, to explore its possible mechanism by establishing4T1mouse breast cancer model, in order to provide experimental basis for enriching the treatment means of breast cancer and expanding the application range of exercise in the prevention and treatment of breast cnncer.
Methods
Six to eight-week-old female BALB/c mice were randomly assigned into two groups of normal control (N,8animals) and model (96animals).For the transplantable tumor model studies, viable4T1breast cancer cells were injected s. c. into the right axilla of BALB/c mice.5days after inoculation, the mice were randomized into six groups:①saline-only (C),②paclitaxel-only(P),③exercise-only in low-intensity (E1),④exercise-only in moderate-intensity(E2),⑤exercise in low-intensity and paclitaxel (EP1),⑥exercise in moderate-intensity and paclitaxel (EP2), with16animals per group. The mice of P, EP1and EP2group received i.p. injections of paclitaxel (20mg/kg/w) during the whole experimental period. The mice of other groups received same volume of saline. Exercise groups performed progressive treadmill running up to12m/min or17m/min at0%grade for30minutes,5d/wk for5weeks.
Results
1. viable4T1breast cancer cells were injected s. c. into the right axilla of BALB/c mice.5days after inoculation, all mice bore tumor. Model was successfully established. The pathological examination revealed that there was invasive breast cancer. All receptors of estrogen, progestoner, human epidermal growth factor receptor--2are negative.
2. After inoculation, the weight of mice loss. The weight of mice in each group of model were significantly lower than weight of mice in N group. There were no significant difference in weight between model mice.
3. The survival time of mice was prolonged in the group of P、EP1、 EP and E2, The time was significantly longer in EP2than other groups.
4. The weight of tumor^tumor volume and ratio of tumor weight and weight of mice were significantly lower in EP2group than C group. There were no significantly difference between other groups and C group.
5. The percentage of regulatory T cell in lymphnode of mice was significantly higher in model groups than N group. The percentage of regulatory T cell in tumor and lymphnode of mice were significantly lower in EP2group than C and P group.
6. The expression of transforming growth factor-β1and interleukin10of mice were significantly lower in EP2.
7. The percentages of S phase was significantly lower and rate of early and late apoptosis cells of mice were significantly higher in EP2.
8. The expression of nuclear factor-kappaB p65. phospho-inhibitory subunit of κB-α of mice were lower in EP2. The expression of p-IκBα of mice was also lower in EP1and E2group, and the effect on p-IκB was better in EP1and EP2than P group, moreover, the effect on p-IκB was better in E2than E1group.
Conclusion
1. The survival time of mice was longer in E2,17m/min moderate intensity exercise can prolong the survival time with tumors in vivo for mice.
2.17m/min moderate intensity exercise combined with paclitaxel can effectively inhibit the growth of tumor, the intervention effect of exercise、paclitaxel alone is ineffective.17m/min moderate intensity Exercise may enhance the anti-cancer effect of paclitaxel.
3. One of mechanisms of exercise combined with paclitaxel may have a role in tumor growth is that exercise may down-regulated the expression of NF-κ Bp65and P-IκBα, reduce proliferation of tumor cells, reduce the percentage of regulatory T cell in tumor and lymphnode of mice, weaken the immune escape of tumor cells, induce apoptosis of tumor cells.
引文
[1]Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J Clin,2011, 61 (2):69-90
[2]Jemal A, Siegel R-Xu J, et al. Cancer Statistics,2010. CA Cancer J Clin,2010,60(5): 277-300
[3]Siegel R, Naishadham D, Jemal A. Cancer Statistics,2012. CA Cancer J Clin 2012,62 (?):10-29
[4]DeSantis C, Siegel R, Bandi P, et al. Breast Cancer Statistics,2011. CA Cancer J Clin, 2011,61 (6):409-418
[5]徐光炜,胡永昇,阚秀.中国10万妇女乳腺癌筛查初探.中国肿癌,2010,19(9)：565-568
[6]任讯.乳腺癌发病率居我国城市女性肿瘤首位.中国医药报,2010,2月/4日/第A04版.
[7]Baud V; Karin M. Is NF-κB a good target for cancer therapy? Hopes and pitfalls. Nature Reviews Drug Discovery,2009,8 (1):33-40
[8]Lin Y, Bai L, Chen W, et al. The NF-κB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opinion on Therapeutic Targets,2010,14 (i): 45-55
[9]Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting:from immunosurveillance to tumor escape, nature immunology,2002,3 (11):991-998
[10]Perez SA. Karamouzis MV, SkarlosDV, et al. CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients. Clin Cancer Res,2007,13 (9):2714-2721
[11]徐兵河.乳腺癌.北京：北京大学医学出版社,2005
[12]Chodzko-Zajko WJ, Proctor DN. Fiatarone Singh MA, et al. Exercise and Physical Activity for Older Adults. Medicine & Science in Sports & Exercise,2009,41 (7): 1510-1530
[13]Graf C, Platen P. Sport and Breast Cancer—The Value of Physical Activity in the Primary and Secondary Prevention of Mammary Carcinomas. European Journal of Sport Science, 2002,2 (5):1-10
[14]Bernstein L, Patel AV, Ursin G, et al. Lifetime Recreational Exercise Activity and Breast Cancer Risk Among Black Women and White Women. Journal of the National Cancer Institute,2005,97 (22):1671-1679
[15]Sternfeld B, Weltzien E, Quesenberry CP, et al. Physical activity and risk of recurrence and mortality in breast cancer survivors:findings from the LACE study. Cancer Epidemiol Biomarkers Prev,2009,18 (1):87-95
[16]Jones LW, Viglianti BL, Tashjian JA, et al. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. Journal of Applied Physiology,2010,108 (2): 343-348
[17]李少林,任国胜,陈晓品,等.乳腺癌的基础理论和临床实践.北京：科学出版社,2008
[18]Parkin DM, F Bray, Ferlay J, Ferlay J, et al. Global Cancer Statistics,2002. CA Cancer J Clin,2005,55:74-108
[19]陈可欣,何敏,董淑芬,等.天津市女性乳腺癌发病率死亡率和生存率分析.中华肿瘤杂志,2002,24(6)：573-575
[20]王启俊,祝伟星,邢秀梅.北京城区女性乳腺癌发病死亡和生存情况20年监测分析.中华肿痈杂志,2006,28(3)：208-2]0
[21]何丹丹,工春芳,曹莉莉,等.上海市闵行区女性乳腺癌发病流行趋势分析.中国肿瘤,2010,19(2)：108-110
[22]刘小芹,钱梦华,邹弘,等.上海市虹口区2007年恶性肿瘤发病情况分析.现代预防医学,2010,37(20)：3975-3976
[23]Sinha R, Gustafson DR, Kulldorff M, et al.2-Amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine, a Carcinogen in High-Temperature-Cooked Meat, and Breast Cancer Risk. JNCI J Natl Cancer Inst,2000,92 (16):1352-1354
[24]Zheng W, Gustafson DR, Moore D, et al. Well-Done Meat Intake and the Risk of Breast Cancer. JNCI J Natl Cancer Inst,1998,90 (22):1724-1729
[25]Ronckers CM, Erdmann CA, Land CE. Radiation and breast cancer:a review of current evidence. Breast Cancer Res,2005,7 (1):21-32
[26]Piek JMJ, Torrenga B, Hermsen B, et al. Histopathological characteristics of BRCA-1 and BRCA-2 associated intraperitoneal cancer:a clinic-based study. Familial Cancer,2003, 2 (2):73-78
[27]Friedenson B. BRCA1 and BRCA2 Pathways and the Risk of Cancers Other Than Breast or Ovarian. MedGenMed,2005,7 (2):60
[28]McPherson K, Steel CM, Dixon JM. Breast cancer-epidemiology, risk factors, and genetics. BMJ,2000,321 (7261):624-628
[29]Brinton LA, Sherman ME, Carreon JD, et al. Recent Trends in Breast Cancer Among Younger Women in the United States. JNCI J Natl Cancer Inst,2008,100 (22): 1643-1648
[30]Santen RJ, Boyd NF, Chlebowski RT, et al. Critical assessment of new risk factors for breast cancer:considerations for development of an improved risk prediction model. Endocr Relat Cancer,2007,14:169-187
[31]Ozmen V, Ozcinar B, Karanlik H. Breast cancer risk factors in Turkish women-a University Hospital based nested case control study. World Journal of Surgical Oncology, 2009,7:37
[32]徐雅莉,孙强,单广良,等.中国女性乳腺癌发病相关危险因素：病例对照研究.协 和医学杂志,2011,2(1)：7-14
[33]Wu MH, Chou YC, Chou WY, et al. Relationships between critical period of estrogen exposure and circulating levels of insulin-like growth factor-1 (IGF-Ⅰ) in breast cancer: evidence from a case-control study. International Journal of Cancer,2010,126 (2): 508-514
[34]Hankinson SE, Eliassen AH. Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk. Journal of Steroid Biochemistry & Molecular Biology,2007, 106:24-30
[35]Clemons M, Goss P. Estrogen and the risk of breast cancer. New England Journal of Medicine,2001,344 (4):276-286.
[36]Fortunati N. Catalano MG, Boccuzzi G, et al. Sex Hormone Binding Globulin (SHBG), Estradiol And Breast Cancer. Molecular and Cellular Endocrinology.2009,316(1):86-92
[37]Yager JD, Davidson NE. Estrogen Carcinogenesis in Breast Cancer. New England Journal of Medicine,2006,354:270-282
[38]杨洁,韩为东,赵业力.雌激素与乳腺癌.现代肿瘤医学,2007,15(3)：431-433
[39]Missmer SA, Eliassen AH, Barbieri RL, et al. Endogenous Estrogen, Androgen, and Progesterone Concentrations and Breast Cancer Risk Among Postmenopausal Women. JNCI J Natl Cancer Inst,2004,96 (24):1856-1865
[40]Eliassen AH, Missmer SA, Tworoger SS, et al. Endogenous Steroid Hormone Concentrations and Risk of Breast Cancer Among Premenopausal Women. JNCI J Natl Cancer Inst,2006,98 (19):1406-1415
[41]Cauley JA, Lucas FL, Kuller LH, et al. Elevated Serum Estradiol and Testosterone Concentrations Are Associated with a High Risk for Breast Cancer. Ann Intern Med, 1999,130 (4):270-277
[42]Sieri S, Krogh V, Bolelli G, et al. Sex Hormone Levels, Breast Cancer Risk, and Cancer Receptor Status in Postmencpausal Women:the ORDET Cohort. Cancer Epidemiol Biomarkers Prev,2009,18 (1):169-176
[43]Macedo.LF, Guo Z, Tilghman SL, et al. Role of Androgens on MCF-7 Breast Cancer Cell Growth and on the Inhibitory Effect of Letrozole. Cancer Res,2006,66 (15):7775-7782
[44]刘季芳,祁岩超.肿瘤免疫编辑研究进展.广东医学,2009,30(10)：1579-1581
[45]Rose DP, Vona-Davis L. Interaction between menopausal status and obesity in affecting breast cancer risk. Maturitas,2010,66 (1):33-38
[46]郑杰.肿瘤的细胞和分子生物学.上海：上海科学技术出版社,2011
[47]Bingham SA, Luben R, Welch A, et al. Are imprecise methods obscuring a relation between fat and breast cancer? Lancet.2003,362:212-214
[48]Freedman LS, Potischman N, Kipnis V, et al. A comparison of two dietary instruments for evaluating the fat-breast cancer relationship. International Journal of Epidemiology,2006, 35:1011-1021
[49]Sieri S, Krogh V, Ferrari P, et al. Dietary fat and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr,2008,88 (5): 1304-1312
[50]Freedman LS, Kipnis V, Schatzkin A, et al. Methods of Epidemiology:Evaluating the Fat-Breast Cancer Hypothesis-Comparing Dietary Instruments and Other Developments. Cancer J,2008,14 (2):69-74
[51]Gago-Dominguez M, Yuan JM, Sun CL, et al. Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study. Br J Cancer, 2003,89 (9):1686-1692
[52]Rose DP. Effects of dietary fatty acids on breast and prostate cancers:evidence from in vitro experiments and animal studies. Am J Clin Nutr,1997,66(6):1513S-1522S
[53]Slattery ML, Curtin K-Giuliano AR, et al. Active and passive smoking, IL6, ESR1, and breast cancer risk. Breast Cancer Res Treat,2008,109(1):101-111
[54]Ahern TP, Lash TL, Egan KM, et al. Lifetime tobacco smoke exposure and breast cancer incidence. Cancer Causes and Control,2009,20 (10):1837-1844
[55]Pirie K, Beral V, Peto R, et al. Passive smoking and breast cancer in never smokers: prospective study and meta-analysis. Int. J. Epidemiol.2008,37 (5):1069-1079
[56]马骏,聂胜男,史本玲,等.被动吸烟与乳腺癌相关性的荟萃分析.中国肿瘤,2011,20(7)：525-528
[57]Johnson KC, Miller AB, Collishaw NE, et al. Active smoking and secondhand smoke increase breast cancer risk:the report of the Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk (2009). Tob Control,2011,20 (1):e2
[58]Narod S A. Alcohol and Risk of Breast Cancer. JAMA,2011,306 (17):1920-1921
[59]Chen WY, Rosner B, Hankinson SE, et al. Moderate Alcohol Consumption During Adult Life, Drinking Patterns, and Breast Cancer Risk. JAMA,2011,306 (17):1884-1890
[60]王启俊,李玲,祝伟星,等.北京市乳腺癌危险因素病例对照研究.中国慢性病预防与控制,2000,8(4)：165-167
[61]王启俊,李玲,祝伟星,等.中国城市居民乳腺癌危险因素的研究.中华流行病学杂志,2000,21(3)：216-220
[62]Badger T, Segrin C, Dorros SM, et al. Depression and Anxiety in Women With Breast Cancer and Their Partners. Nursing Research,2007,56 (1):44-53
[63]Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature,2000,406 (17):747-752
[64]Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA,2003,100 (14): 8418-8423
[65]Carey LA, Perou CM, LivasyCA, et al. Race, Breast Cancer Subtypes, and Survival in the Carolina Breast Cancer Study. JAMA,2006,295 (21):2492-2502
[66]Foulkes WD, Smith IE, Reis-Filho JS. Triple-Negative Breast Cancer. N Engl J Med, 2010,363:1938-1948
[67]李慧,姜达.三阴性乳腺癌的研究进展.肿瘤基础与临床,2011,24(6)：540-543
[68]孙燕.肿瘤综合治疗的原则和进展.第15届全国肿瘤内科治疗学习班及学术研讨会论文集,2005：1-17
[69]方志沂.乳腺癌.北京：北京大学医学出版社,2007
[70]Sparano JA, Wang M, Martino S, et al. Weekly Paclitaxel in the Adjuvant Treatment of Breast Cancer. N Engl J Med,2008,358 (16):1663-1671
[71]何裕民.现代中医肿瘤学.北京：中国协和医科大学出版社,2005
[72]王正珍,冯炜权,任弘,等Exercise is Medicin——健身新理念.北京体育大学学报,2010,33(11)：1-4
[73]Viatour P, Merville MP, Bours V, et al. Phosphorylation of NF-kappaB and IkappaB proteins:implications in cancer and inflammation. Trends In Biochemical Sciences,2005, 30 (1):43-52
[74]Sovak MA, Bellas RE, Kim DW, et al. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. The Journal Of Clinical Investigation,1997,100 (12): 2952-2960
[75]Karin M. Nuclear factor-KB in cancer development and progression. Nature,2006,441: 431-436
[76]Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell,1986,46 (5):705-716
[77]Hayden S, Ghosh S. Signaling to NF-κB. Genes & Dev,2004.18:2195-2224
[78]Gilmore TD. Introduction to NF-κB:players, pathways, perspectives. Oncogene,2006, 25:6680-6684
[79]Kumar A, Takada Y, Boriek AM, et al. Nuclear factor-KB:its role in health and disease. Journal of Molecular Medicine,2004,82 (7):434-448
[80]Roman-Blas JA, Jimenez SA. Targeting NF-κB:A Promising Molecular Therapy in Inflammatory Arthritis. International Reviews of Immunology,2008.27 (5):351-374
[81]Frasor J, Weaver A, Pradhan M, et al. Positive Cross-Talk between Estrogen Receptor and NF-κB in Breast Cancer. Cancer Res,2009,69 (23),8918-8925
[82]邓元,张学斌,王鸿雁,等.乳腺癌组织中核转录因子NF-κB和抑癌基因p53的表达及其意义.肿瘤防治研究,2007,34(5)：342-344
[83]Huber MA, Azoitei N, Baumann B, et al. NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest,2004,114 (4):569-581
[84]Kim DW, Sovak MA, Zanieski G, et al. Activation of NF-kappaB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis,2000,21 (5):871-879
[85]Hsu SM, Chen YC, Jiang MC.17β-Estradiol Inhibits Tumor Necrosis Factor-a-Induced Nuclear Factor-KB Activation by Increasing Nuclear Factor-KB p105 Level in MCF-7 Breast Cancer Cells. Biochemical and Biophysical Research Communications,2000,279 (1):47-52
[86]Dunn GP, Old LJ, Schreiber RD. The Three Es of Cancer Immunoediting. Annual Review of Immunology,2004,22:329-360
[87]吴霞,李大金.肿瘤免疫编辑.现代免疫学,2005,25(6)：518-521
[88]Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews Cancer,2005,5:263-274
[89]Sakaguchi S, Sakaguchi N, Asano M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol,1995,155 (3):1151-1164
[90]Zou W. Regulatory T cells-tumour immunity and imunotherapy. Nature Reviews Immunology,2006,6:295-307
[91]何裕民.癌症只是慢性病.上海：上海科学技术出版社,2008
[92]王树堂.“带瘤生存”为癌症治疗带来新观念——周岱翰教授诠释中医肿瘤学.新中医,2009,41(7)：107-108
[93]Young-Mcaughan S, Arzola SM. Exercise intervention research for patients with cancer on treatment. Semin Oncol Nurs,2007,23 (4):264-274
[94]Sallis RE.Exercise is medicine and physicians need to prescribe it! British Journal of Sports Medicine,2009,43 (1):3-4
[95]Anderson RL. Understanding Breast Cancer Risk. Radiologic Technology,2010:81 (5): 457M-476M
[96]Stasiolek D, Kwasniewska M, Drygas W. Breast cancer:selected risk factors, primary prevention. Przegl Lek,2002,59 (1):26-30
[97]唐晓义,戎晶晶,甄志平.身体活动降低罹患乳腺癌风险的生物学机制研究进展.体育科学,2011,31(7)：79-84
[98]Frisch RE, Wyshak G, Albright NL, et al. Lower prevalence of breast cancer and cancers of the reproductive system among former college athletes compared to non-athletes. Br J Cancer,1985,52 (6):885-891
[99]Wyshak G, Frisch RE.Breast cancer among former college athletes compared to non-athletes:a 15-year follow-up. Br J Cancer,2000,82 (3):726-730
[100]Peters TM, Schatzkin A, Gierach GL, et al. Intensity and timing of physical activity in relation to postmenopausal breast cancer risk:the prospective NIH-AARP Diet and Health Study. BMC Cancer,2009,9:349-362
[101]Eliassen AH, Hankinson SE, Rosner B, et al. Physical Activity and Risk of Breast Cancer Among Postmenopausal Women. Arch Intern Med,2010,170 (19):1758-1764 [102] Margolis KL., Mucci L, Braaten T, et al. Physical Activity in Different Periods of Life and the Risk of Breast Cancer:The Norwegian-Swedish Women's Lifestyle and Health Cohort Study. Cancer Epidemiol Biomarkers Prev,2005,14 (1):27-32
[103]王玉.早期运动干预对二甲基苯蒽诱导大鼠乳腺癌发生影响的研究.现代预防医学,2008,35(14)：27282729
[104]Friedenreich CM, Courneya KS, Bryant HE. Relation between intensity of physical activity and breast cancer risk reduction. Med Sic Sports Exerc,2001,33 (9):1538-1545
[105]Peplonska B, Lissowska J, Hartman TJ. et al. Adulthood lifetime physical activity and breast cancer. Epidemiology (Cambridge, Mass),2008,19 (2):226-236
[106]Lima C De, Alves LE, lagher F, et al. Anaerobic exercise reduces tumor growth, cancer cachexia and increases macrophage and lymphocyte response in Walker 256 tumor-bearing rat. Eur J Appl Physiol,2008,104:957-964
[107]蒲劲松,王玉,刘彦娜,等.运动对MNU诱发大鼠乳腺癌的影响.四川大学学报(医学版),2008,39(2)：320-322
[108]Thompson HJ, Ronan AM, Ritacco KA, et al. Effect of Exercise on the Induction of Mammary Carcinogenesis. Cancer Res,1988,48:2720-2723
[109]Jones LW, Eves ND, Courneya KS, et al. Effects of Exercise Training on Antitumor Efficacy of Doxorubicin in MDA-MB-231 Breast Cancer Xenografts. Clin Cancer Res, 2005,11 (18):6695-6698
[110]Thompson HJ. Effect of Exercise Intensity and Duration on the Induction of Mammary Carcinogenesis. Cancer Res,1994,54:1960s-1963s
[111]Zielinski MR, Muenchow M, Wallig MA, et al. Exercise delays allogeneic tumor growth and reduces intratumoral inflammation and vascularization. Journal of Applied Physiology,2004,96 (6):2249-2256
[112]Boudreau N, Myers C. Breast cancer-induced angiogenesis:multiple mechanisms and the role of the microenvironment. Breast Cancer Res,2003,5 (3):140-146
[113]Keays KS, Harris SR, Lucyshyn JM, et al. Effects of Pilates Exercises on Shoulder Range of Motion, Pain, Mood, and Upper-Extremity Function in Women Living With Breast Cancer:A Pilot Study. Physical Therapy,2008,88 (4):494-510
[114]王运良,孙翔云,王亚斌,等.太极拳运动对乳腺癌患者术后患肢功能及生活质量的影响.中国体育科技,2010,46(5)：125-127
[115]Rogers LQ, Courneya KS, Shah P, et al. Exercise stage of change, barriers, expectations, values and preferences among breast cancer patients during tieatment:a pilot study. European Journal of Cancer Care,2007,16 (1):55-66
[116]Fairey AS, Courneya KS, Field CJ, et al. Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors. Journal of Applied Physiology,2005,98 (4):1534-1540
[117]Hsieh CC, Sprod LK, Hydock DS, et al. Effects of a Supervised Exercise Intervention on Recovery From Treatment Regimens in Breast Cancer Survivors. Oncol Nurs Forum, 2008,35 (6):909-915
[118]Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy:a multicenter randomized controlled trial. J Clin Oncol,2007,25 (28):4396-4404
[119]McNeely ML, CampbellKL, Rowe BH, et al. Effects of exercise on breast cancer patients and survivors:a systematic review and meta-analysis. CMAJ,2006,175 (1):34-41
[120]Daley AJ, Crank H, Saxton JM, et al. Randomized Trial of Exercise Therapy in Women Treated for Breast Cancer. JCO,2007,25 (13):1713-1721
[121]Irwin ML, Smith AW, Mctiernan A, et al. Influence of pre-and post diagnosis physical activity on mortality in breast cancer survivors:the health, eating, activity, and lifestyle study. J Clin Oncol,2008,26 (24):3958-3964
[122]Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival after breast cancer diagnosis. JAMA,2005,293 (20):2479-2486
[123]Holick CN, Newcomb PA, Trentham-Dietz A, et al. Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomarkers Prev,2008,17 (2): 379-386
[124]McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer,2008, 8 (3):205-211
[125]Goodwin PJ, Ennis M, Pritchard KI. et al. Fasting insulin and outcome in early-stage breast cancer:results of a prospective cohort study. J Clin Oncol,2002,20(1):42-51
[126]Irwin ML, McTiernan A, Bernstein L, et al. Relationship of obesity and physical activity with C-peptide, leptin, and insulin-like growth factors in breast cancer survivors. Cancer Epidemiol Biomarkers Prev,2005,14 (12):2881-2888
[127]Kroenke CH, Chen WY, Rosner B, et al. weight gain, and survival after breast cancer diagnosis. J Clin Oncol,2005,23 (7):1370-1378
[128]Sternfeld B, Weltzien E, Quesenberry CP, et al. Physical activity and risk of recurrence and mortality in breast cancer survivors:findings from the LACE study. Cancer Epidemiol Biomarkers Prev,2009,18 (1):87-95
[129]Knols R, Aaronson NK, Uebelhart D, et al. Physical Exercise in Cancer Patients During and After Medical Treatment:A Systematic Review of Randomized and Controlled Clinical Trials. JCO,2005,23 (16):3830-3842
[130]Campbell KL, Neil SE, Winters-Stone. Review of exercise studies in breast cancer survivors:attention to principles of exercise training. Br J Sports Med,2011
[131]Courneya KS. Physical activity in cancer survivors:a field in motion. Psycho-Oncology, 2009,18 (4):337-342
[132]Rogers CJ, Colbert LH, Greiner JW, et al. Physical Activity and Cancer Prevention: Pathways and Targets for Intervention. Sports Med,2008,38 (4):271-296
[133]Malin A, Matthews CE, Shu XO, et al. Energy Balance and Breast Cancer Risk. Cancer Epidemiol Biomarkers,2005 14:1496-1501
[134]Silvera SAN, Jain M, Howe GR, et al. Energy balance and breast cancer risk:a prospective cohort study. Breast cancer research and Treatment,2006,97 (1):97-106
[135]Richardson CR, Newton TL. A Meta-Analysis of Pedometer-Based Walking Interventions and Weight Loss. Ann Fam Med,2008,6 (1):69-77
[136]Mustelin L, Silventoinen K, Pietilainen K, et al. Physical activity reduces the influence of genetic effects on BMI and waist circumference:a study in young adult twins. I nternational Journal of Obesity,2009.33 (1):29-36
[137]Monninkhof EM, Velthuis MJ, Peeters PHM, et al. Effect of Exercise on Postmenopausal Sex Hormone Levels and Role of Body Fat:A Randomized Controlled Trial. JCO,2009, 27 (27):4492-4499
[138]Friedenreich CM, Woolcott CG. Alberta Physical Activity and Breast Cancer Prevention Trial:Sex Hormone Changes in a Year-Long Exercise Intervention Among Postmenopausal Women. JCO,2010,28 (9):1458-1466
[139]Brolinson PG, Elliott D. Exercise and the Immune System. Clin Sports Med,2007,26 (3):311-319
[140]陈佩杰.运动免疫学研究进展.体育科学,2000,20(6)：41-46
[141]Drela N, Kozdron E, Szczypiorski P.Moderate exercise may attenuate some aspects of immunosenescence. BMC Geriatrics,2004,4:8
[142]Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis,2010, 31 (1):9-18
[143]DePinho RA, Polyak K. Cancer chromosomes in crisis. Nature genetics,2004,36(9): 932-934
[144]Shammas MA. Telomeres, lifestyle, cancer, and aging. Current Opinion in Clinical Nutrition and Metabolic Care,2011,14(1):28-34
[145]Ludlow AT, Zimmerman JOB, Witkowski S. Relationship between Physical Activity Level, Telomere Length, and Telomerase Activity. Med Sci Sports Exerc.2008,40 (10): 1764-1771
[146]Cherkas LF, Hunkin JL, Kato BS, et al. The Association Between Physical Activity in Leisure Time and Leukocyte Telomere Length. Arch Intern Med,2008,168 (2):154-158
[147]Gomez-Cabrera MC, Domenech E, Vina.1. Moderate exercise is an antioxidant: Upregulation of antioxidant genes by training. Free Radical Biology & Medicine,2008, 44 (2):126-131
[148]Nakamoto H, Kaneko T, Tahara S, et al. Regular exercise reduces 8-oxodG in the nuclear and mitochondrial DNA and modulates the DNA repair activity in the liver of old rats. Exp Gerontol,2007,42 (4):287-295
[149]Coussens LM, Werb Z. Inflammation and cancer. Nature,2002,420 (6917):860-867
[150]Grivennikov SI, Greten FR, Karin M. Immunity, Inflammation, and Cancer. Cell.2010, 140 (6):883-899
[151]ll'yasova D, Colbert LH, Harris TB, et al. Circulating Levels of Inflammatory Markers and Cancer Risk in the Health Aging and Body Composition Cohort. Cancer Epidemiol Biomarkers Prev,2005,14(10):2413-2418
[152]Pierce BL, Ballard-Barbash R, Bernstein L, etal. Elevated Biomarkers of Inflammation Are Associated With Reduced Survival Among Breast Cancer Patients. JCO,2009,27 (21):3437-3444
[153]Mathur N, Pedersen BK. Exercise as a Mean to Control Low-Grade Systemic Inflammation. Mediators of Inflammation,2008,2008 (2)
[154]Nicklas BJ, Hsu FC, Brinkley TJ, et al. Exercise Training and Plasma C-reactive Protein and Interleukin-6 in the Elderly. J Am Geriatr Soc,2008,56(11):2045-2052
[155]陈庆永.陈道达.核因子-KB与乳腺癌的研究进展.国外医学外科学分册,2004,31(3)：150-152
[156]Radak Z, Chung HY, Naito H, et al. Age-associated increase in oxidative stress and nuclear factor κB activation are attenuated in rat liver by regular exercise. The FASEB Journal,2004,18 (6):749-750
[157]徐林,蒋正刚,李宝华,等.小鼠乳腺癌实验动物模型中CD4+CD25+调节性T细胞的变化及意义.复旦学报(医学版),2006,33(6)：736-739
[158]Fernando P, Bonen A, Hoffman-Goetz L. Predicting submaximal oxygen consumption during treadmill running in mice. Canadian Journal of Physiology and Pharmacology, 1993,71:854-857
[!59]Nam JS, Terabe M, Kang MJ,et al. Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17. Cancer Res,2008,68 (10):3915-3923
[160]纪小龙,张雷.诊断免疫组织化学.北京：人民军医出版社,2011
[161]许良中,杨文涛.免疫组织化学反应结果的判断标准.中国癌症杂志,1996,6(4)：229-231
[162]汪家政,范明.蛋白质技术手册.北京：科学出版社,2000
[163]汪谢丹.重组HSP70-4T1肿瘤抗原肽修饰树突状细胞的抗肿瘤作用：[博士学位论文].武汉：华中科技大学,2007
[164]梁智辉,朱慧芬,陈九武.流式细胞术基本原理与实用技术.武汉：华中科技大学出版社,2008
[165]贾艳华,吴 荻.乳腺癌动物模型建立与应用的进展.中国肿瘤,2009,18 (11)：900-904
[166]孙靖.实验动物学基础.北京：北京科学技术出版社,2005
[167]Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol,2001, Chapter 20:Unit 20 2
[168]Nam JS, Terabe M, Kang MJ, et al. Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17. Cancer Res, 2008,68 (10):3915-3923
[169]Hiraga T, Williams PJ, Ueda A, et al. Zoledronic Acid Inhibits Visceral Metastases in the 4T1/luc Mouse Breast Cancer Model. Clin Cancer Res,2004,10:4559-4567
[170]http://www.vitalriver.com.cn/article/show.php?itemid=42&page=1
[171]魏泓.医学实验动物学.成都：四川科学技术出版社,1998
[172]Catia M, Robertsonal MD, Morganal LM. Effects of exercise and restrained eating behaviouron appetite control. Proceedings of the Nutrition Society,2008,67:28-41
[173]汪军.运动对摄食量和体重的影响.基础医学与临床,2009,29(7)：771-774
[174]Nabholtz JM, Gligorov J. The role of taxanes in the treatment of breast cancer. Expert Opin Pharmacother,2005,6 (7):1073-1094
[175]Sasvari M, Taylor AW, Gaal D, et al. The effect of regular exercise on development of sarcoma tumor and oxidative damage in mice liver. Journal of Sports Science and Medicine,2011,10:93-96
[176]马智超.运动联合载药纳米粒靶向给药系统应用于肿瘤治疗的探索性研究：[硕士学位论文].扬州：扬州大学,2010
[177]孙海双.临床统计方法及SPSS应用.北京：科学出版社,2009
[178]Nakagomi H, Petersson M, Magnusson I, etal. Colorectal Carcinoma Tumor-infiltrating T Cells and NK Cells of Patients with Chains in ζ Decreased Expression of the Signal-transducing. Cancer research,1993,53 (23):5610-5612
[179]Gangi E, Vasu C, Cheatem D, et al. IL-10-Producing CD4+ CD25+ Regulatory T Cells Play a Critical Role in Granulocyte-Macrophage Colony-Stimulating Factor-Induced Suppression of Experimental Autoimmune Thyroiditis.The Journal of Immunology,2005, 174 (11):7006-7013
[180]Antony PA, Restifo NP.Do CD4+ CD25+ Immunoregulatory T Cells Hinder Tumor Immunotherapy? J Immunother,2002,25 (3):202-206
[181]Merlo A, Casalini P, Carcangiu ML, et al. FOXP3 Expression and Overall Survival in Breast Cancer. ICO,2009,27 (11):1746-1752
[182]钟华韩宝惠.紫杉醇通过上调TAP-1, TAP-2以及消除调节性T细胞逆转肺癌免疫逃逸.L中国肺癌杂志,2010,13(10)：937-941
[183]Yeh SH, Chuang H, Lin LW, et al. Regular tai chi chuan exercise enhances functional mobility and CD4CD25 regulatory T cells. British Journal of Sports Medicine,2006,40 (3):239-243
[184]工茹,陈佩杰CD4+CD25+调节性T细胞在大鼠递增负荷过度训练中的表达及其免疫调节功能.上海体育学院学报,2010,34(3)：49-51
[185]宋红利.不同强度运动对小鼠CD4+CD25+调节性T细胞及核酸疫苗免疫效果影响的研究：[硕士学位论文].河南：河南大学,2010
[186]汪继兵.自控锻炼对癌症长期生存者的健康状况及生活质量影响的研究：[博士学位论文].上海：上海体育学院,2010
[187]Nakamura K, Kitani A, Fuss I, et al. TGF-β1 Plays an Important Role in the Mechanism of CD4+CD25+ Regulatory T Cell Activity in Both Humans and Mice. The Journal of Immunology,2004,172 (2):834-842
[188]Piek E, Roberts A. Suppressor and oncogenic roles of transforming growth factor-β and its signaling pathways in tumorigenesis. Advances in Cancer Research,2001,83:1-54
[189]Portugal J, Bataller M, Mansilla S. Cell death pathways in response to antitumor therapy. Tumori,2009,95 (4):409-421
[190]Schlotter CM, Vogt U, Allgayer H, et al. Molecular targeted therapies for breast cancer treatment. Breast Cancer Res,2008,10 (4):211
[191]French JP, Hamilton KL. Quindry JC, et al. Exercise-induced protection against myocardial apoptosis and necrosis:MnSOD, calcium-handling proteins, and calpain. The FASEB Journal,2008,22 (8):2862-2871
[192]Phaneuf S, Leeuwenburgh C. Apoptosis and exercise. Medicine & Science in Sports & Exercise,2001,33 (3):393-396
[193]陈伟,樊新生,张廷妍,等.不同强度力竭运动大鼠运动后12h肝细咆凋亡的研究.北京体育大学学报,2010,33(2)：59-63
[194]Biswas DK, Shi Q, Baily S, et al. NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci USA,2004,101 (27): 10137-10142
[195]陈艳梅,郝选明.运动训练对核转录因子kappaB信号通路及炎性基因影响的研究进展.体育学刊,2011,18(3)：140-144
[196]尹荟菁,程联胜.基因工程抗体增强紫杉醇诱导乳腺癌细胞SKBr3凋亡的作用.中国免疫学杂志,2007,23(3)：229-233
