title: In vivo and in vitro evidence that PPARγ ligands are antagonists of leptin signaling in breast cancer.
abstract: Obesity is a major risk factor for the development and progression of breast cancer. Leptin, a cytokine mainly produced by adipocytes, plays a crucial role in mammary carcinogenesis and is elevated in hyperinsulinemia and insulin resistance. The antidiabetic thiazolidinediones inhibit leptin gene expression through ligand activation of the peroxisome proliferator-activated receptor-γ (PPARγ) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPARγ ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models. The results show that activation of PPARγ prevented the development of leptin-induced MCF-7 tumor xenografts and inhibited the increased cell-cell aggregation and proliferation observed on leptin exposure. PPARγ ligands abrogated the leptin-induced up-regulation of leptin gene expression and its receptors in breast cancer. PPARγ-mediated repression of leptin gene involved the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors corepressors on the glucocorticoid responsive element site in the leptin gene expression regulatory region in the presence of glucocorticoid receptor and PPARγ. In addition, PPARγ ligands inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation and counteracted leptin stimulatory effect on estrogen signaling. These findings suggest that PPARγ ligands may have potential therapeutic benefits in the treatment of breast cancer.
authors.affiliation: Department of Pharmaco-Biology, University of Calabria, Arcavacata, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Loredana
authors.initials: L
authors.lastname: Mauro
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Michele
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.forename: Pietro
authors.initials: P
authors.lastname: Rizza
authors.forename: Donatella
authors.initials: D
authors.lastname: Vizza
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bossi
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020738:Leptin / Q000378:metabolism*; D008024:Ligands; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009765:Obesity / Q000150:complications; D047495:PPAR gamma / Q000378:metabolism*; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D020738:Leptin; D008024:Ligands; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D011988:Receptors, Thyroid Hormone