TY - JOUR
T1 - Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis
AU - Taliaferro-Smith, La Tonia
AU - Nagalingam, Arumugam
AU - Knight, Brandi Brandon
AU - Oberlick, Elaine
AU - Saxena, Neeraj K.
AU - Sharma, Dipali
N1 - Funding Information:
Address all correspondence to: Dipali Sharma, PhD, Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB 1, Rm 145, Baltimore, MD 21231. E-mail: dsharma7@jhmi.edu or Neeraj Saxena, Department of Medicine, University of Maryland School of Medicine, 660 W Redwood St, Howard Hall, Rm 301, Baltimore, MD 21201. E-mail: nsaxena@medicine.umaryland.edu 1This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) National Institute of Health (NIH) (K01DK076742 and R03DK089130; to N.K.S.), National Cancer Institute (NCI) NIH (R01CA131294), Safeway Foundation, Avon Foundation, and Breast Cancer Research Foundation (90047965; to D.S.). There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. 2This article refers to supplementary materials, which are designated by Figures W1 to W5 and are available online at www.neoplasia.com. 3Co-first author. Received 9 September 2012; Revised 21 November 2012; Accepted 3 December 2012 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.121502
PY - 2013/1
Y1 - 2013/1
N2 - The molecular effects of obesity aremediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nudemice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.
AB - The molecular effects of obesity aremediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nudemice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.
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U2 - 10.1593/neo.121502
DO - 10.1593/neo.121502
M3 - Article
C2 - 23358729
AN - SCOPUS:84873052595
SN - 1522-8002
VL - 15
SP - 23
EP - 38
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 1
ER -