Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line.
Leptin, a product of adipocytes, is involved in the regulation of body weight and results strongly correlated to body fat content. An excess of fat mass represents a breast cancer risk factor particularly in postmenopausal women, where estrogen production by adipose tissue through its own aromatase activity stimulates tumor progression. Leptin stimulates estrogen production through the increase of aromatase expression and activity in human luteinized granulosa cells and adipose stromal cells. In the present study, we have examined the possible link that exists between leptin and breast cancer, focusing our attention on the direct effect of leptin on aromatase activity, which may enhance estrogen production and induce tumor cell growth stimulation. We have shown that leptin enhances aromatase mRNA expression, aromatase content, and its enzymatic activity in MCF-7. Aromatase expression appears to be regulated by tissue-specific promoter. It has been demonstrated that promoters II and 1.3 are the major promoters that drive aromatase expression in MCF-7. Transient transfection experiments using vector containing human aromatase promoters II and 1.3 sequence fused with luciferase reporter gene demonstrated that leptin is able to activate this promoter. In the presence of either mitogen-activated protein kinase inhibitor PD 98059 or ERK2 dominant negative as well as in the presence of STAT3 dominant negative, the stimulatory effects of leptin on aromatase promoter, enzymatic activity, and aromatase protein content were inhibited. Functional studies of mutagenesis and electrophoretic mobility shift assay revealed that the AP-1 motif is important in determining the up-regulatory effects induced by leptin on aromatase expression in MCF-7.
Catalano
Stefania
S
Centro Sanitario and the Department of PharmacoBiology, Faculty of Pharmacy, University of Calabria, 87030 Arcavacata di Rende, Italy.
Marsico
Stefania
S
Giordano
Cinzia
C
Mauro
Loredana
L
Rizza
Pietro
P
Panno
Maria Luisa
ML
Andò
Sebastiano
S
D000735:Androstenedione / Q000378:metabolism; D001141:Aromatase / Q000032:analysis / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000502:physiology; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D020738:Leptin; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D000735:Androstenedione; D004958:Estradiol; D004247:DNA; D008156:Luciferases; D001141:Aromatase; D020928:Mitogen-Activated Protein Kinases