Abstract
Obesity is considered the most important risk and prognostic factor for estrogen-dependent breast cancer in postmenopausal women. Adipokines, in particular leptin, are at the center of the etiopathogenetic mechanisms by which obesity and related metabolic disorders influence breast cancer risk and its prognosis. The present prospective observational study aims to investigate the relationship between body mass index (BMI), serum levels of leptin and proinflammatory cytokines, and breast cancer prognostic factors. In the study, 98 postmenopausal and 82 premenopausal patients with ER-positive breast cancer participated. During the same study period, 221 control subjects were simultaneously recruited. Women underwent baseline measurements pre-operatively, before any surgical and systemic treatments. Pathologic characteristics of tumors were abstracted from pathology reports. Leptin and proinflammatory cytokines were assayed in stored fasting blood specimens. In postmenopausal breast cancer patients, BMI, leptin, and interleukin-6 significantly correlated with pathological tumor classification (pT) and TNM stage. Multivariate regression analysis showed that BMI and leptin, but not interleukin-6, were independent predictive variables of pT and TNM stage. Our results seem to suggest a twofold role of leptin in the etiopathogenesis of postmenopausal estrogen-positive breast cancer. Indeed, leptin reflects the total amount of fat mass, which correlates to aromatase activity and subsequent estrogens levels. Further studies are warranted to clarify the role of leptin and interleukin-6 in breast carcinogenesis and identify new therapeutic options, beyond the use of aromatase inhibitors, acting selectively on adipokine-driven pathways.
Similar content being viewed by others
References
Jensen EV, Jordan VC (2003) The estrogen receptor: a model for molecular medicine. Clin Cancer Res 9:1980–1989
Key TJ, Appleby PN, Reeves GK (2003) Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218–1226
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638
Berclaz G, Li S, Price KN, Coates AS, Castiglione-Gertsch M, Rudenstam CM, Holmberg SB, Lindtner J, Erien D, Collins J et al (2004) Body mass index as a prognostic feature in operable breast cancer: the International Breast Cancer Study Group experience. Ann Oncol 15:875–884
MacDonald PC, Edman CD, Hemsell DL, Porter JC, Siiteri PK (1978) Effect of obesity on conversion of plasma androstenedione to estrone in postmenopausal women with and without endometrial cancer. Am J Obstet Gynecol 130:448–455
Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5:153–165
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 90:1292–1299
Stephenson GD, Rose DP (2003) Breast cancer and obesity: an update. Nutr Cancer 45:1–16
Dizdar O, Alyamaç E (2004) Obesity: an endocrine tumor? Med Hypotheses 63:790–792
Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556
Vona-Davis L, Rose DP (2007) Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 14:189–206
Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S et al (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1:1155–1161
Simons PJ, van den Pangaart PS, van Roomen CP, Aerts JM, Boon L (2005) Cytokine-mediated modulation of leptin and adiponectin secretion during in vitro adipogenesis: evidence that tumor necrosis factor-alpha- and interleukin-1beta-treated human preadipocytes are potent leptin producers. Cytokine 32:94–103
Margetic S, Gazzola C, Pegg GG, Hill RA (2002) Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26:1407–1433
Clark GM, McGuire WL (1983) Progesterone receptors and human breast cancer. Breast Cancer Res Treat 3:157–163
Hu X, Juneja SC, Maihle NJ, Cleary MP (2002) Leptin-a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 94:1704–1711
Sulkowska M, Golaszewska J, Wincewicz A, Koda M, Baltaziak M, Sulkowski S (2006) Leptin-from regulation of fat metabolism to stimulation of breast cancer growth. Pathol Oncol Res 12:69–72
Cleary MP, Juneja SC, Phillips FC, Hu X, Grande JP, Maihle NJ (2004) Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors. Exp Biol Med (Maywood) 229:182–193
Ishikawa M, Kitayama J, Nagawa H (2004) Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res 10:4325–4331
Catalano S, Mauro L, Marsico S, Giordano C, Rizza P, Rago V, Montanaro D, Maggiolini M, Panno ML, Andó S (2004) Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 279:19908–19915
Miyoshi Y, Funahashi T, Tanaka S, Taguchi T, Tamaki Y, Shimomura I, Noguchi S (2006) High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels. Int J Cancer 118:1414–1419
Magoffin DA, Weitsman SR, Aagarwal SK, Jakimiuk AJ (1999) Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling women. Ginekol Pol 70:1–7
Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, Fu OY, Chen HY, Hou MF, Yuan SS (2006) Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 237:109–114
Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, Andò S (2003) Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 278:28668–28676
Yin N, Wang D, Zhang H, Yi X, Sun X, Shi B, Wu H, Wu G, Wang X, Shang Y (2004) Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin. Cancer Res 64:5870–5875
Tessitore L, Vizio B, Pesola D, Cecchini F, Mussa A, Argiles JM, Benedetto C (2004) Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients. Int J Oncol 24:1529–1535
Wu MH, Chou YC, Chou WY, Hsu GC, Chu CH, Yu CP, Yu JC, Sun CA (2009) Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer 100:578–582
Cust AE, Stocks T, Lukanova A, Lundin E, Hallmans G, Kaaks R, Jonsson H, Stattin P (2009) The influence of overweight and insulin resistance on breast cancer risk and tumor stage at diagnosis: a prospective study. Breast Cancer Res Treat 113:567–576
Goodwin PJ, Ennis M, Fantus IG, Pritchard KI, Trudeau ME, Koo J, Hood N (2005) Is leptin a mediator of adverse prognostic effects of obesity in breast cancer? J Clin Oncol 23:6037–6042
Han C, Zhang HT, Du L, Liu X, Jing J, Zhao X, Yang X, Tian B (2005) Serum levels of leptin, insulin, and lipids in relation to breast cancer in China. Endocrine 26:19–24
Petridou E, Papadiamantis Y, Markopoulos C, Spanos E, Dessypris N, Trichopoulos D (2000) Leptin and insulin growth factor I in relation to breast cancer (Greece). Cancer Causes Control 11:383–388
Coskun U, Günel N, Toruner FB, Sancak B, Onuk E, Bayram O, Cengiz O, Yilmaz E, Elbeg S, Ozkan S (2003) Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer. Neoplasma 50:41–46
Sauter ER, Garofalo C, Hewett J, Hewett JE, Morelli C, Surmacz E (2004) Leptin expression in breast nipple aspirate fluid (NAF) and serum is influenced by body mass index (BMI) but not by the presence of breast cancer. Horm Metab Res 36:336–340
Woo HY, Park H, Ki CS, Park YL, Bae WG (2006) Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea. Cancer Lett 237:137–142
Goodwin PJ (2008) Host-related factors in breast cancer: an underappreciated piece of the puzzle? J Clin Oncol 26:3299–3300
Barnett GC, Shah M, Redman K, Easton DF, Ponder BA, Pharoah PD (2008) Risk factors for the incidence of breast cancer: do they affect survival from the disease? J Clin Oncol 26:3310–3316
Stattin P, Söderberg S, Biessy C, Lenner P, Hallmans G, Kaaks R, Olsson T (2004) Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat 86:191–196
Mantzoros CS, Bolhke K, Moschos S, Cramer DW (1999) Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls. Int J Cancer 80:523–526
Geisler J, Haynes B, Ekse D, Dowsett M, Lønning PE (2007) Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels. J Steroid Biochem Mol Biol 104:27–34
Macciò A, Madeddu C, Mantovani G (2009) Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives. Obes Rev 10:660–670
Tanaka M, Nakaya S, Kumai T, Watanabe M, Tateishi T, Shimizu H, Kobayashi S (2001) Effects of estrogen on serum leptin levels and leptin mRNA expression in adipose tissue in rats. Horm Res 56:98–104
Garofalo C, Sisci D, Surmacz E (2004) Leptin interferes with the effects of the antiestrogen ICI 182, 780 in MCF-7 breast cancer cells. Clin Cancer Res 10:6466–6475
Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13:279–292
Purohit A, Newman SP, Reed MJ (2002) The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer. Breast Cancer Res 4:65–69
Singh A, Purohit A, Duncan LJ, Mokbel K, Ghilchik MW, Reed MJ (1997) Control of aromatase activity in breast tumors: the role of the immune system. J Steroid Biochem Mol Biol 61:185–192
Purohit A, Singh A, Ghilchik MW, Serlupi-Crescenzi O, Reed MJ (2003) Inhibition of IL-6 + IL-6 soluble receptor-stimulated aromatase activity by the IL-6 antagonist, Sant 7, in breast tissue-derived fibroblasts. Br J Cancer 88:630–635
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808
Walter M, Liang S, Ghosh S, Hornsby PJ, Li R (2009) Interleukin 6 secreted from adipose stromal cells promotes migration and invasion of breast cancer cells. Oncogene 28:2745–2755
Macciò A, Madeddu C, Massa D, Astara G, Farci D, Melis GB, Mantovani G (2009) Interleukin-6 and leptin as markers of energy metabolic changes in advanced ovarian cancer patients. J Cell Mol Med 13(9B):3951–3959. doi:10.1111/j.1582-4934.2008.00408
Macciò A, Madeddu C, Massa D, Mudu MC, Lusso MR, Gramignano G, Serpe R, Melis GB, Mantovani G (2005) Hemoglobin levels correlate with interleukin-6 levels in patients with advanced untreated epithelial ovarian cancer: role of inflammation in cancer-related anemia. Blood 106:362–367
Mantovani G, Macciò A, Madeddu C, Mura L, Massa E, Mudu MC, Mulas C, Lusso MR, Gramignano G, Piras MB (2001) Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites. J Mol Med 79:406–414
Acknowledgments and Disclosure Statement
This work was supported by “Associazione sarda per la ricerca in oncologia ginecologica ONLUS”. The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Macciò, A., Madeddu, C., Gramignano, G. et al. Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: preliminary results and therapeutic implications. J Mol Med 88, 677–686 (2010). https://doi.org/10.1007/s00109-010-0611-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-010-0611-8