TY - JOUR
T1 - Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo
AU - Park, Jiyoung
AU - Kusminski, Christine M.
AU - Chua, Streamson C.
AU - Scherer, Philipp E.
N1 - Funding Information:
Supported by NIH grants R01-DK55758, R01-CA112023, P01DK088761 (P.E.S.), and DK081182 (Jay Horton) and post-doctoral fellowship from the Department of Defense ( USAMRMC BC085909 to J.P. ) and from the Juvenile Diabetes Foundation ( JDRF 3-2008-130 to C.M.K. ) as well as the New York Nutrition Obesity Research Center , P01 DK2667 .
PY - 2010/12
Y1 - 2010/12
N2 - Obesity represents a risk factor for certain types of cancer. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. A direct physiological role of peripheral leptin action in the tumor microenvironment in vivo has not yet been examined. Here, we report that mice deficient in the peripheral leptin receptor, while harboring an intact central leptin signaling pathway, develop a fully mature ductal epithelium, a phenomenon not observed in db/db mice to date. In the context of the MMTV-PyMT mammary tumor model, the lack of peripheral leptin receptors attenuated tumor progression and metastasis through a reduction of the ERK1/2 and Jak2/STAT3 pathways. These are tumor cell-autonomous properties, independent of the metabolic state of the host. In the absence of leptin receptor signaling, the metabolic phenotype is less reliant on aerobic glycolysis and displays an enhanced capacity for β-oxidation, in contrast to nontransformed cells. Leptin receptor-free tumor cells display reduced STAT3 tyrosine phosphorylation on residue Y705 but have increased serine phosphorylation on residue S727, consistent with preserved mitochondrial function in the absence of the leptin receptor. Therefore, local leptin action within the mammary gland is a critical mediator, linking obesity and dysfunctional adipose tissue with aggressive tumor growth.
AB - Obesity represents a risk factor for certain types of cancer. Leptin, a hormone predominantly produced by adipocytes, is elevated in the obese state. In the context of breast cancer, leptin derived from local adipocytes is present at high concentrations within the mammary gland. A direct physiological role of peripheral leptin action in the tumor microenvironment in vivo has not yet been examined. Here, we report that mice deficient in the peripheral leptin receptor, while harboring an intact central leptin signaling pathway, develop a fully mature ductal epithelium, a phenomenon not observed in db/db mice to date. In the context of the MMTV-PyMT mammary tumor model, the lack of peripheral leptin receptors attenuated tumor progression and metastasis through a reduction of the ERK1/2 and Jak2/STAT3 pathways. These are tumor cell-autonomous properties, independent of the metabolic state of the host. In the absence of leptin receptor signaling, the metabolic phenotype is less reliant on aerobic glycolysis and displays an enhanced capacity for β-oxidation, in contrast to nontransformed cells. Leptin receptor-free tumor cells display reduced STAT3 tyrosine phosphorylation on residue Y705 but have increased serine phosphorylation on residue S727, consistent with preserved mitochondrial function in the absence of the leptin receptor. Therefore, local leptin action within the mammary gland is a critical mediator, linking obesity and dysfunctional adipose tissue with aggressive tumor growth.
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U2 - 10.2353/ajpath.2010.100595
DO - 10.2353/ajpath.2010.100595
M3 - Article
C2 - 21056997
AN - SCOPUS:78650187530
SN - 0002-9440
VL - 177
SP - 3133
EP - 3144
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -