Journal of Breast Cancer

Korean Breast Cancer Society (한국유방암학회)
권호 표지
DOI QR코드

DOI QR Code

Leptin as a Potential Target for Estrogen Receptor-Positive Breast Cancer

  • Yom, Cha Kyong (Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine) ;
  • Lee, Kyung-Min (Cancer Research Institute and Department of Surgery, Seoul National University College of Medicine) ;
  • Han, Wonshik (Cancer Research Institute and Department of Surgery, Seoul National University College of Medicine) ;
  • Kim, Sung-Won (Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine) ;
  • Kim, Hee Sung (Department of Pathology, Chung-Ang University College of Medicine) ;
  • Moon, Byung In (Department of Surgery, Ewha Womans University School of Medicine) ;
  • Jeong, Ku-Young (Department of Surgery, Ewha Womans University School of Medicine) ;
  • Im, Seock-Ah (Cancer Research Institute and Department of Surgery, Seoul National University College of Medicine) ;
  • Noh, Dong-Young (Cancer Research Institute and Department of Surgery, Seoul National University College of Medicine)
  • Received : 2013.01.08
  • Accepted : 2013.04.02
  • Published : 2013.06.30
⟨ Previous Next ⟩

Abstract

Purpose: Leptin is a potent adipokine that plays a significant role in tumor development and the progression of breast cancer. The aim of this study was to evaluate whether leptin affects the response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancer cells. Methods: Leptin, leptin receptor (Ob-R), and activation of signaling pathways were studied by Western immunoblotting. The effects of leptin on tamoxifen-dependent growth inhibition were studied in MCF-7 and T-47D cells. Results: Leptin was expressed in MCF-7 and T-47D and had a proliferative effect on MCF-7 cells. Leptin significantly inhibited the antiestrogenic effect of tamoxifen in both cells only under ${\beta}$-estradiol (E2) (20 nM) conditions. In MCF-7, the inhibitory effect against tamoxifen was a result from the activation of the ERK1/2 and STAT3 signal transduction pathway. Conclusion: Leptin interferes with the effects of tamoxifen under E2 stimulated conditions in ER-positive breast cancer cells. These results imply that inhibition of leptin is expected to enhance the response to tamoxifen in ER-positive breast cancer cells, and, therefore, could be a promising way to overcome endocrine resistance.

Keywords

References

  1. Reinier KS, Vacek PM, Geller BM. Risk factors for breast carcinoma in situ versus invasive breast cancer in a prospective study of pre- and post-menopausal women. Breast Cancer Res Treat 2007;103:343-8. https://doi.org/10.1007/s10549-006-9375-9
  2. Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003;95:1218-26. https://doi.org/10.1093/jnci/djg022
  3. Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 2007;14:189-206. https://doi.org/10.1677/ERC-06-0068
  4. Pischon T, Nothlings U, Boeing H. Obesity and cancer. Proc Nutr Soc 2008;67:128-45. https://doi.org/10.1017/S0029665108006976
  5. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 2007;67:2497-507. https://doi.org/10.1158/0008-5472.CAN-06-3075
  6. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263-71. https://doi.org/10.1016/0092-8674(95)90151-5
  7. Bjørbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997;272:32686-95. https://doi.org/10.1074/jbc.272.51.32686
  8. Yamashita T, Murakami T, Otani S, Kuwajima M, Shima K. Leptin receptor signal transduction: OBRa and OBRb of fa type. Biochem Biophys Res Commun 1998;246:752-9. https://doi.org/10.1006/bbrc.1998.8689
  9. Garofalo C, Koda M, Cascio S, Sulkowska M, Kanczuga-Koda L, Golaszewska J, et al. Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res 2006;12:1447-53. https://doi.org/10.1158/1078-0432.CCR-05-1913
  10. Rose DP, Gilhooly EM, Nixon DW. Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review). Int J Oncol 2002;21:1285-92.
  11. Catalano S, Marsico S, Giordano C, Mauro L, Rizza P, Panno ML, et al. Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line. J Biol Chem 2003;278:28668-76. https://doi.org/10.1074/jbc.M301695200
  12. Kitawaki J, Kusuki I, Koshiba H, Tsukamoto K, Honjo H. Leptin directly stimulates aromatase activity in human luteinized granulosa cells. Mol Hum Reprod 1999;5:708-13. https://doi.org/10.1093/molehr/5.8.708
  13. Spicer LJ, Francisco CC. The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function. Endocrinology 1997;138:3374-9. https://doi.org/10.1210/endo.138.8.5311
  14. Ghizzoni L, Barreca A, Mastorakos G, Furlini M, Vottero A, Ferrari B, et al. Leptin inhibits steroid biosynthesis by human granulosa-lutein cells. Horm Metab Res 2001;33:323-8. https://doi.org/10.1055/s-2001-15419
  15. Machinal-Quelin F, Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. Direct in vitro effects of androgens and estrogens on ob gene expression and leptin secretion in human adipose tissue. Endocrine 2002;18:179-84. https://doi.org/10.1385/ENDO:18:2:179
  16. Bennett PA, Lindell K, Karlsson C, Robinson IC, Carlsson LM, Carlsson B. Differential expression and regulation of leptin receptor isoforms in the rat brain: effects of fasting and oestrogen. Neuroendocrinology 1998;67:29-36. https://doi.org/10.1159/000054295
  17. Lindell K, Bennett PA, Itoh Y, Robinson IC, Carlsson LM, Carlsson B. Leptin receptor 5'untranslated regions in the rat: relative abundance, genomic organization and relation to putative response elements. Mol Cell Endocrinol 2001;172:37-45. https://doi.org/10.1016/S0303-7207(00)00382-8
  18. Garofalo C, Sisci D, Surmacz E. Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells. Clin Cancer Res 2004;10:6466-75. https://doi.org/10.1158/1078-0432.CCR-04-0203
  19. Catalano S, Mauro L, Marsico S, Giordano C, Rizza P, Rago V, et al. Leptin induces, via ERK1/ERK2 signal, functional activation of estrogen receptor alpha in MCF-7 cells. J Biol Chem 2004;279:19908-15. https://doi.org/10.1074/jbc.M313191200
  20. Hu X, Juneja SC, Maihle NJ, Cleary MP. Leptin: a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 2002;94:1704-11. https://doi.org/10.1093/jnci/94.22.1704
  21. Surmacz E. Obesity hormone leptin: a new target in breast cancer? Breast Cancer Res 2007;9:301. https://doi.org/10.1186/bcr1638
  22. Chen X, Zha X, Chen W, Zhu T, Qiu J, Roe OD, et al. Leptin attenuates the anti-estrogen effect of tamoxifen in breast cancer. Biomed Pharmacother 2013;67:22-30. https://doi.org/10.1016/j.biopha.2012.10.001
  23. Binai NA, Damert A, Carra G, Steckelbroeck S, Löwer J, Löwer R, et al. Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells. Int J Cancer 2010;127:55-66. https://doi.org/10.1002/ijc.25010
  24. Marsaud V, Gougelet A, Maillard S, Renoir JM. Various phosphorylation pathways, depending on agonist and antagonist binding to endogenous estrogen receptor alpha (ERalpha), differentially affect ERalpha extractability, proteasome-mediated stability, and transcriptional activity in human breast cancer cells. Mol Endocrinol 2003;17:2013-27. https://doi.org/10.1210/me.2002-0269
  25. Onuma M, Bub JD, Rummel TL, Iwamoto Y. Prostate cancer cell-adipocyte interaction: leptin mediates androgen-independent prostate cancer cell proliferation through c-Jun NH2-terminal kinase. J Biol Chem 2003;278:42660-7. https://doi.org/10.1074/jbc.M304984200
  26. Rouet-Benzineb P, Aparicio T, Guilmeau S, Pouzet C, Descatoire V, Buyse M, et al. Leptin counteracts sodium butyrate-induced apoptosis in human colon cancer HT-29 cells via NF-kappaB signaling. J Biol Chem 2004;279:16495-502. https://doi.org/10.1074/jbc.M312999200
  27. Bouloumié A, Drexler HC, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis. Circ Res 1998;83:1059-66. https://doi.org/10.1161/01.RES.83.10.1059
  28. Tessitore L, Vizio B, Jenkins O, De Stefano I, Ritossa C, Argiles JM, et al. Leptin expression in colorectal and breast cancer patients. Int J Mol Med 2000;5:421-6.
  29. Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, Fu OY, et al. Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 2006;237:109-14. https://doi.org/10.1016/j.canlet.2005.05.047
  30. Madaio RA, Spalletta G, Cravello L, Ceci M, Repetto L, Naso G. Overcoming endocrine resistance in breast cancer. Curr Cancer Drug Targets 2010;10:519-28. https://doi.org/10.2174/156800910791517226

Cited by

  1. Inhibition of Leptin and Leptin Receptor Gene Expression by Silibinin-Curcumin Combination vol.14, pp.11, 2013, https://doi.org/10.7314/apjcp.2013.14.11.6595
  2. The Multifaceted Mechanism of Leptin Signaling within Tumor Microenvironment in Driving Breast Cancer Growth and Progression vol.4, pp.None, 2013, https://doi.org/10.3389/fonc.2014.00340
  3. ObRb downregulation increases breast cancer cell sensitivity to tamoxifen vol.36, pp.9, 2015, https://doi.org/10.1007/s13277-015-3375-5
  4. Relationship of obesity with serum concentrations of leptin, CRP and IL-6 in breast cancer survivors vol.27, pp.4, 2013, https://doi.org/10.1016/j.jnci.2015.09.001
  5. Mammary Adipose Tissue-Derived Lysophospholipids Promote Estrogen Receptor–Negative Mammary Epithelial Cell Proliferation vol.9, pp.5, 2013, https://doi.org/10.1158/1940-6207.capr-15-0107
  6. Obesity and Breast Cancer: Role of Leptin vol.9, pp.None, 2019, https://doi.org/10.3389/fonc.2019.00596
  7. Combination of Silibinin and Curcumin Reduced Leptin Receptor Expression in MCF-7 Human Breast Cancer Cell Line vol.45, pp.6, 2013, https://doi.org/10.30476/ijms.2019.81934
  8. Autophagy Mediates Leptin-Induced Migration and ERK Activation in Breast Cancer Cells vol.9, pp.None, 2021, https://doi.org/10.3389/fcell.2021.644851
  9. Obesity, leptin, and deregulation of microRNA in lipid metabolisms: their contribution to breast cancer prognosis vol.13, pp.None, 2021, https://doi.org/10.1186/s13098-020-00621-4