Zusammenfassung
Fragestellung Einer Reihe von epidemiologischen Erhebungen zufolge besteht ein erhöhtes Risikopotenzial
übergewichtiger Frauen nach der Menopause an Brustkrebs zu erkranken. Eine einheitliche
Erklärung für den Zusammenhang zwischen Adipositas und Tumorerkrankungen existiert
bislang nicht. Neuere Forschungsansätze konzentrieren sich auf die Untersuchung verschiedener
Biomarker der Adipositas, deren Veränderungen auch Auswirkungen auf die Tumorpathogenese
haben können. Dazu zählen Östrogene und Androgene, das „sex hormone-binding globulin”,
Insulin und eine Insulinresistenz sowie aus Fettzellen freigesetzte Mediatoren mit
endokriner Aktivität. Die mögliche Rolle dieser Biomarker bei der Entstehung und der
Progression eines Mammakarzinoms sowie ihre Beeinflussbarkeit durch Lebensstilveränderungen
sollen im folgenden Übersichtsartikel dargestellt werden. Methoden Review der Literatur zu Änderungen der genannten Biomarker durch Lebensstilveränderungen.
Der Fokus der zitierten Untersuchungen liegt dabei auf dem Gebiet der Primärprävention,
da nur in einzelnen Fällen Studien mit Mammakarzinompatientinnen durchgeführt wurden.
Ergebnisse Ernährungsverhalten oder körperliche Aktivität werden als unterstützende Maßnahme
im Hinblick auf eine Verbesserung der Lebensqualität wahrgenommen, können darüber
hinaus jedoch auch als ein Mechanismus verstanden werden, der die Rezidiv- oder Überlebensrate
mitbestimmt. Es gibt Hinweise auf günstige Veränderungen der Serumspiegel von Insulin,
„Insulin-like growth factor” und anderen Biomarkern durch Lebensstilveränderungen.
Schlussfolgerung Diese Parameter bieten sich als wertvolle Werkzeuge für zukünftige Studien an, die
sich mit den Auswirkungen einer positiven Lebensstilveränderung auf pathogenetische
Mechanismen bei Brustkrebspatientinnen beschäftigen.
Abstract
Purpose Epidemiological data provide evidence that there is an increased risk for obese women
to develop post-menopausal breast cancer. Hazardous lifestyle patterns may increase
cancer risk by several mechanisms. These include a changed pattern of biomarkers of
obesity, e. g. estrogens and androgens, hyperinsulinemia and insulin resistance, and
endocrine functions of adipose tissue. It is the aim of this review to summarize the
actual knowledge of the potential role of selected biological markers of obesity in
breast cancer development and progression as well as their affection by lifestyle
modifications. Methods Review of the literature on the changes of these biomarkers by lifestyle modifications.
Results To the extent that lifestyle factors have been a focus of cancer prognosis studies,
they have often been aimed at the question of whether they impact quality of life.
Moreover, interventional programs may influence cancer survival or recurrence. Evidence
points towards a beneficial modulation of biological obesity markers like insulin
or insulin-like growth factor via lifestyle changes. Conclusion Thus, these parameters may provide a valuable tool for future studies dealing with
the effects of positive lifestyle modifications on breast cancer risk and survival.
Schlüsselwörter
Adipositas - Biomarker - Lebensstilmodifikation - Mammakarzinom - Übergewicht
Key words
adipositas - biomarker - breast cancer - lifestyle intervention - overweight
Literatur
- 1
Stephenson G D, Rose D P.
Breast cancer and obesity: an update.
Nutr Cancer.
2003;
45
1-16
- 2
Cui Y, Whiteman M K, Flaws J A. et al .
Body mass and stage of breast cancer at diagnosis.
Int J Cancer.
2002;
98
279-283
- 3
Morimoto L M, White E, Chen Z. et al .
Obesity, body size, and risk of postmenopausal breast cancer: the Women's Health Initiative
(United States).
Cancer Causes Control.
2002;
13
741-751
- 4
Brinton L A, Swanson C A.
Height and weight at various ages and risk of breast cancer.
Ann Epidemiol.
1992;
2
597-609
- 5
Trentham-Dietz A, Newcomb P A, Storer B E. et al .
Body size and risk of breast cancer.
Am J Epidemiol.
1997;
145
1011-1019
- 6
Parker E D, Folsom A R.
Intentional weight loss and incidence of obesity-related cancers: the Iowa Women's
Health Study.
Int J Obes Relat Metab Disord.
2003;
27
1447-1452
- 7 International Agency for Research on Cancer .Handbooks of cancer prevention Vol.
6: weight control and physical activity. Lyon; World Health Organization 2002
- 8
Catalano M G, Frairia R, Boccuzzi G. et al .
Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in
breast cancer cells.
Mol Cell Endocrinol.
2005;
230
31-37
- 9
Dieudonne M N, Machinal-Quelin F, Serazin-Leroy V. et al .
Leptin mediates a proliferative response in human MCF7 breast cancer cells.
Biochem Biophys Res Commun.
2002;
293
622-628
- 10
Papa V, Belfiore A.
Insulin receptors in breast cancer: biological and clinical role.
J Endocrinol Invest.
1996;
19
324-333
- 11
Purohit A, Newman S P, Reed M J.
The role of cytokines in regulating estrogen synthesis: implications for the etiology
of breast cancer.
Breast Cancer Res.
2002;
4
65-69
- 12
Yamauchi T, Kamon J, Minokoshi Y. et al .
Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating
AMP-activated protein kinase.
Nat Med.
2002;
8
1288-1295
- 13
Zhang X, Yee D.
Tyrosine kinase signalling in breast cancer: insulin-like growth factors and their
receptors in breast cancer.
Breast Cancer Res.
2000;
2
170-175
- 14
Lawlor D A, Smith G D, Ebrahim S.
Hyperinsulinaemia and increased risk of breast cancer: findings from the British Women's
Heart and Health Study.
Cancer Causes Control.
2004;
15
267-275
- 15
de Cabo R, Furer-Galban S, Anson R M. et al .
An in vitro model of caloric restriction.
Exp Gerontol.
2003;
38
631-639
- 16
Barnard R J, Gonzalez J H, Liva M E. et al .
Effects of a low-fat, high-fiber diet and exercise program on breast cancer risk factors
in vivo and tumor cell growth and apoptosis in vitro.
Nutr Cancer.
2006;
55
28-34
- 17
Liu Y M, Lacorte J M, Viguerie N. et al .
Adiponectin gene expression in subcutaneous adipose tissue of obese women in response
to short-term very low calorie diet and refeeding.
J Clin Endocrinol Metab.
2003;
88
5881-5886
- 18
Houmard J A, Tanner C J, Slentz C A. et al .
Effect of the volume and intensity of exercise training on insulin sensitivity.
J Appl Physiol.
2004;
96
101-106
- 19
Watkins L L, Sherwood A, Feinglos M. et al .
Effects of exercise and weight loss on cardiac risk factors associated with syndrome
X.
Arch Intern Med.
2003;
163
1889-1895
- 20
Renehan A G, Zwahlen M, Minder C. et al .
Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic
review and meta-regression analysis.
Lancet.
2004;
363
1346-1353
- 21
Maccario M, Aimaretti G, Grottoli S. et al .
Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with
simple obesity. Comparison with normal subjects and hypopituitary patients with severe
GH deficiency.
Int J Obes Relat Metab Disord.
2001;
25
1233-1239
- 22
Smith A T, Clemmons D R, Underwood L E. et al .
The effect of exercise on plasma somatomedin-C/insulinlike growth factor I concentrations.
Metabolism.
1987;
36
533-537
- 23
Snyder D K, Clemmons D R, Underwood L E.
Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects
on anabolism, lipolysis, and body composition.
J Clin Endocrinol Metab.
1988;
67
54-61
- 24
Barnard R J, Ngo T H, Leung P S. et al .
A low-fat diet and/or strenuous exercise alters the IGF axis in vivo and reduces prostate
tumor cell growth in vitro.
Prostate.
2003;
56
201-206
- 25
Fairey A S, Courneya K S, Field C J. et al .
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.
2003;
12
721-727
- 26
Asikainen T M, Miilunpalo S, Kukkonen-Harjula K. et al .
Walking trials in postmenopausal women: effect of low doses of exercise and exercise
fractionization on coronary risk factors.
Scand J Med Sci Sports.
2003;
13
284-292
- 27
McTiernan A, Tworoger S S, Ulrich C M. et al .
Effect of exercise on serum estrogens in postmenopausal women: a 12-month randomized
clinical trial.
Cancer Res.
2004;
64
2923-2928
- 28
Bernstein L, Ross R K.
Endogenous hormones and breast cancer risk.
Epidemiol Rev.
1993;
15
48-65
- 29
Key T, Appleby P, Barnes I. et al .
Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine
prospective studies.
J Natl Cancer Inst.
2002;
94
606-616
- 30
McTiernan A, Wu L, Chen C. et al .
Relation of BMI and physical activity to sex hormones in postmenopausal women.
Obesity.
2006;
14
1662-1677
- 31
Verkasalo P K, Thomas H V, Appleby P N. et al .
Circulating levels of sex hormones and their relation to risk factors for breast cancer:
a cross-sectional study in 1092 pre- and postmenopausal women (United Kingdom).
Cancer Causes Control.
2001;
12
47-59
- 32
Tanko L B, Bruun J M, Alexandersen P. et al .
Novel associations between bioavailable estradiol and adipokines in elderly women
with different phenotypes of obesity: implications for atherogenesis.
Circulation.
2004;
110
2246-2252
- 33
Beitins I Z, Barkan A, Klibanski A. et al .
Hormonal responses to short-term fasting in postmenopausal women.
J Clin Endocrinol Metab.
1985;
60
1120-1126
- 34
Bagga D, Ashley J M, Geffrey S P. et al .
Effects of a very low fat, high fiber diet on serum hormones and menstrual function.
Implications for breast cancer prevention.
Cancer.
1995;
76
2491-2496
- 35
Micheli A, Muti P, Secreto G. et al .
Endogenous sex hormones and subsequent breast cancer in premenopausal women.
Int J Cancer.
2004;
112
312-318
- 36
Kaaks R, Bellati C, Venturelli E. et al .
Effects of dietary intervention on IGF-I and IGF-binding proteins, and related alterations
in sex steroid metabolism: the Diet and Androgens (DIANA) Randomised Trial.
Eur J Clin Nutr.
2003;
57
1079-1088
- 37
Hainer V, Kunesova M, Sonka J. et al .
The effect of a short-term reducing regimen on hormonal secretion in obese patients.
Cas Lek Cesk.
1989;
128
1006-1011
- 38
Turcato E, Zamboni M, De Pergola G. et al .
Interrelationships between weight loss, body fat distribution and sex hormones in
pre- and postmenopausal obese women.
J Intern Med.
1997;
241
363-372
- 39
Tchernof A, Despres J P.
Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women.
Horm Metab Res.
2000;
32
526-536
- 40
Plymate S R, Matej L A, Jones R E. et al .
Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2)
cell line by insulin and prolactin.
J Clin Endocrinol Metab.
1988;
67
460-464
- 41
Fortunati N, Fissore F, Fazzari A. et al .
Estradiol induction of cAMP in breast cancer cells is mediated by foetal calf serum
(FCS) and sex hormone-binding globulin (SHBG).
J Steroid Biochem Mol Biol.
1999;
70
73-80
- 42
Key T, Appleby P, Barnes I. et al .
Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine
prospective studies.
J Natl Cancer Inst.
2002;
94
606-616
- 43
O'Dea J P, Wieland R G, Hallberg M C. et al .
Effect of dietery weight loss on sex steroid binding sex steroids, and gonadotropins
in obese postmenopausal women.
J Lab Clin Med.
1979;
93
1004-1008
- 44
Tymchuk C N, Tessler S B, Barnard R J.
Changes in sex hormone-binding globulin, insulin, and serum lipids in postmenopausal
women on a low-fat, high-fiber diet combined with exercise.
Nutr Cancer.
2000;
38
158-162
- 45
Arita Y, Kihara S, Ouchi N. et al .
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.
Biochem Biophys Res Commun.
1999;
257
79-83
- 46
Mantzoros C, Petridou E, Dessypris N. et al .
Adiponectin and breast cancer risk.
J Clin Endocrinol Metab.
2004;
89
1102-1107
- 47
Miyoshi Y, Funahashi T, Kihara S. et al .
Association of serum adiponectin levels with breast cancer risk.
Clin Cancer Res.
2003;
9
5699-5704
- 48
Gavrila A, Chan J L, Yiannakouris N. et al .
Serum adiponectin levels are inversely associated with overall and central fat distribution
but are not directly regulated by acute fasting or leptin administration in humans:
cross-sectional and interventional studies.
J Clin Endocrinol Metab.
2003;
88
4823-4831
- 49
Imbeault P, Pomerleau M, Harper M E. et al .
Unchanged fasting and postprandial adiponectin levels following a 4-day caloric restriction
in young healthy men.
Clin Endocrinol.
2004;
60
429-433
- 50
Ferguson M A, White L J, McCoy S. et al .
Plasma adiponectin response to acute exercise in healthy subjects.
Eur J Appl Physiol.
2004;
91
324-329
- 51
Yokoyama H, Emoto M, Araki T. et al .
Effect of aerobic exercise on plasma adiponectin levels and insulin resistance in
type 2 diabetes.
Diabetes Care.
2004;
27
1756-1758
- 52
Esposito K, Pontillo A, Di Palo C. et al .
Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese
women: a randomized trial.
JAMA.
2003;
289
1799-1804
- 53
Shadid S, Stehouwer C D, Jensen M D.
Diet/Exercise versus Pioglitazone: Effects of Insulin Sensitization with Decreasing
or Increasing Fat Mass on Adipokines and Inflammatory Markers.
J Clin Endocrinol Metab.
2006;
91
3418-3425
- 54
Petridou E, Papadiamantis Y, Markopoulos C. et al .
Leptin and insulin growth factor I in relation to breast cancer (Greece).
Cancer Causes Control.
2000;
11
383-388
- 55
Stattin P, Soderberg S, Biessy C. et al .
Plasma leptin and breast cancer risk: a prospective study in northern Sweden.
Breast Cancer Res Treat.
2004;
86
191-196
- 56
Tessitore L, Vizio B, Jenkins O. et al .
Leptin expression in colorectal and breast cancer patients.
Int J Mol Med.
2000;
5
421-426
- 57
Jenkins A B, Markovic T P, Fleury A. et al .
Carbohydrate intake and short-term regulation of leptin in humans.
Diabetologia.
1997;
40
348-351
- 58
Haluzik M, Matoulek M, Svacina S. et al .
The influence of short-term fasting on serum leptin levels, and selected hormonal
and metabolic parameters in morbidly obese and lean females.
Endocr Res.
2001;
27
251-260
- 59
Miyawaki T, Masuzaki H, Ogawa Y. et al .
Clinical implications of leptin and its potential humoral regulators in long-term
low-calorie diet therapy for obese humans.
Eur J Clin Nutr.
2002;
56
593-600
- 60
Houmard J A, Cox J H, MacLean P S. et al .
Effect of short-term exercise training on leptin and insulin action.
Metabolism.
2000;
49
858-861
- 61
Reseland J E, Anderssen S A, Solvoll K. et al .
Effect of long-term changes in diet and exercise on plasma leptin concentrations.
Am J Clin Nutr.
2001;
73
240-245
- 62
Thong F S, Hudson R, Ross R. et al .
Plasma leptin in moderately obese men: independent effects of weight loss and aerobic
exercise.
Am J Physiol Endocrinol Metab.
2000;
279
E307-E313
- 63
Hilton L K, Loucks A B.
Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin
in healthy young women.
Am J Physiol Endocrinol Metab.
2000;
278
E43-E49
- 64
Hotamisligil G S, Shargill N S, Spiegelman B M.
Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin
resistance.
Science.
1993;
259
87-91
- 65
Hotamisligil G S, Arner P, Caro J F. et al .
Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity
and insulin resistance.
J Clin Invest.
1995;
95
2409-2415
- 66
Kern P A, Saghizadeh M, Ong J M. et al .
The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity,
weight loss, and relationship to lipoprotein lipase.
J Clin Invest.
1995;
95
2111-2119
- 67
Marfella R, Esposito K, Siniscalchi M. et al .
Effect of weight loss on cardiac synchronization and proinflammatory cytokines in
premenopausal obese women.
Diabetes Care.
2004;
27
47-52
- 68
Lee E C, Zhan P, Schallhom R. et al .
Antiandrogen-induced cell death in LNCaP human prostate cancer cells.
Cell Death Differ.
2003;
10
761-771
- 69
Rozen F, Zhang J, Pollak M.
Antiproliferative action of tumor necrosis factor-alpha on MCF-7 breastcancer cells
is associated with increased insulin-like growth factor binding protein-3 accumulation.
Int J Oncol.
1998;
13
865-869
- 70
do Nascimento C O, Hunter L, Trayhurn P.
Regulation of haptoglobin gene expression in 3T3-L1 adipocytes by cytokines, catecholamines,
and PPARgamma.
Biochem Biophys Res Commun.
2004;
313
702-708
- 71
Purohit A, Reed M J.
Regulation of estrogen synthesis in postmenopausal women.
Steroids.
2002;
67
979-983
- 72
Bastard J P, Jardel C, Bruckert E. et al .
Variations in plasma soluble tumour necrosis factor receptors after diet-induced weight
loss in obesity.
Diabetes Obes Metab.
2000;
2
323-325
- 73
Bastard J P, Hainque B, Dusserre E. et al .
Peroxisome proliferator activated receptor-gamma, leptin and tumor necrosis factor-alpha
mRNA expression during very low calorie diet in subcutaneous adipose tissue in obese
women.
Diabetes Metab Res Rev.
1999;
15
92-98
- 74
Arvidsson E, Viguerie N, Andersson I. et al .
Effects of different hypocaloric diets on protein secretion from adipose tissue of
obese women.
Diabetes.
2004;
53
1966-1971
- 75
Bruun J M, Lihn A S, Verdich C. et al .
Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro
investigations in humans.
Am J Physiol Endocrinol Metab.
2003;
285
E527-E533
- 76
Xydakis A M, Case C C, Jones P H. et al .
Adiponectin, inflammation, and the expression of the metabolic syndrome in obese individuals:
the impact of rapid weight loss through caloric restriction.
J Clin Endocrinol Metab.
2004;
89
2697-2703
- 77
Tsukui S, Kanda T, Nara M. et al .
Moderate-intensity regular exercise decreases serum tumor necrosis factor-alpha and
HbA1c levels in healthy women.
Int J Obes Relat Metab Disord.
2000;
24
1207-1211
- 78
Straczkowski M, Kowalska I, Dzienis-Straczkowska S. et al .
Changes in tumor necrosis factor-alpha system and insulin sensitivity during an exercise
training program in obese women with normal and impaired glucose tolerance.
Eur J Endocrinol.
2001;
145
273-280
- 79
Hayase H, Nomura S, Abe T. et al .
Relation between fat distributions and several plasma adipocytokines after exercise
training in premenopausal and postmenopausal women.
J Physiol Anthropol Appl Human Sci.
2002;
21
105-113
- 80
Ziccardi P, Nappo F, Giugliano G. et al .
Reduction of inflammatory cytokine concentrations and improvement of endothelial functions
in obese women after weight loss over one year.
Circulation.
2002;
105
804-809
- 81
Kim H J, Higashimori T, Park S Y. et al .
Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin
action in vivo.
Diabetes.
2004;
53
1060-1067
- 82
Ryan A S, Nicklas B J.
Reductions in plasma cytokine levels with weight loss improve insulin sensitivity
in overweight and obese postmenopausal women.
Diabetes Care.
2004;
27
1699-1705
- 83
Kern P A, Ranganathan S, Li C. et al .
Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity
and insulin resistance.
Am J Physiol Endocrinol Metab.
2001;
280
E745-E751
- 84
Bastard J P, Jardel C, Bruckert E. et al .
Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue
of obese women after weight loss.
J Clin Endocrinol Metab.
2000;
85
3338-3342
- 85
Colbert L H, Visser M, Simonsick E M. et al .
Physical activity, exercise, and inflammatory markers in older adults: findings from
the Health, Aging and Body Composition Study.
J Am Geriatr Soc.
2004;
52
1098-1104
- 86
Jankord R, Jemiolo B.
Influence of physical activity on serum IL-6 and IL-10 levels in healthy older men.
Med Sci Sports Exerc.
2004;
36
960-964
- 87
Nieman D C, Nehlsen-Cannarella S L, Fagoaga O R. et al .
Effects of mode and carbohydrate on the granulocyte and monocyte response to intensive,
prolonged exercise.
J Appl Physiol.
1998;
84
1252-1259
- 88
Nieman D C, Davis J M, Henson D A. et al .
Carbohydrate ingestion influences skeletal muscle cytokine mRNA and plasma cytokine
levels after a 3-h run.
J Appl Physiol.
2003;
94
1917-1925
- 89
Lyngso D, Simonsen L, Bulow J.
Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect
of exercise.
J Physiol.
2002;
543
373-378
- 90
Keller C, Keller P, Marshal S. et al .
IL-6 gene expression in human adipose tissue in response to exercise - effect of carbohydrate
ingestion.
J Physiol.
2003;
550
927-931
- 91
You T, Berman D M, Ryan A S. et al .
Effects of hypocaloric diet and exercise training on inflammation and adipocyte lipolysis
in obese postmenopausal women.
J Clin Endocrinol Metab.
2004;
89
1739-1746
- 92
Monzillo L U, Hamdy O, Horton E S. et al .
Effect of lifestyle modification on adipokine levels in obese subjects with insulin
resistance.
Obes Res.
2003;
11
1048-1054
PD Dr. Georg Hoffmann
Institut für Urlaubs-, Reise- und Höhenmedizin der Universität für Gesundheitswissenschaften,
Medizinische Informatik und Technik
Eduard Wallnöfer-Zentrum 1
6060 Hall, Österreich
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