In Vivo and in Vitro Evidence That PPAR gamma Ligands Are Antagonists of Leptin Signaling in Breast Cancer

作者：Catalano Stefania; Mauro Loredana; Bonofiglio Daniela; Pellegrino Michele; Qi Hongyan; Rizza Pietro; Vizza Donatella; Bossi Gianluca; Ando Sebastiano^*

来源：American Journal Of Pathology, 2011, 179(2): 1030-1040.

DOI：10.1016/j.ajpath.2011.04.026

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-gamma (PPAR gamma) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPAR gamma ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models. The results show that activation of PPAR gamma prevented the development of leptin-induced MCF-7 tumor xenografts and inhibited the increased cell-cell aggregation and proliferation observed on leptin exposure. PPAR gamma ligands abrogated the leptin-induced up-regulation of leptin gene expression and its receptors in breast cancer. PPAR gamma-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 PPAR gamma. In addition, PPAR gamma ligands inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation and counteracted leptin stimulatory effect on estrogen signaling. These findings suggest that PPAR gamma ligands may have potential therapeutic benefits in the treatment of breast cancer. (Am J Pathol 2011, 179:1030-1040; DOI: 10.1016/j.ajpath.2011.04.026)

• 出版日期2011-8