PPARγ signaling exacerbates mammary gland tumor development

Abstract

Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice

“…Intriguingly, the same study also showed that overproduction of a constitutively active Vp16/PPAR␥ fusion transcription factor in mouse mammary epithelial cells exacerbates PyMT-induced tumorigenesis (51). Although Vp16/PPAR␥ overexpression may significantly alter the balance of cellular concentrations of coactivators and corepressors available for other transcriptional regulators, this study suggests that the mechanisms by which PPAR␥ regulates mammary gland tumorigenesis are extremely complex.…”

“…Third, another study with similar breeding strategy in our laboratory showed a comparable mammary gland tumorigenesis in steroid receptor coactivator-1 Ϫ/Ϫ /PyMT and WT/ PyMT mice (data not shown). Fourth, PPAR␥ ϩ/Ϫ /PyMT and WT/ PyMT mice, generated by crossing mice with C57BL/129SvJ and FVB strain background, also showed no difference in mammary gland tumorigenesis (51).…”

PGC-1α induces apoptosis in human epithelial ovarian cancer cells through a PPARγ-dependent pathway

“…Since PPARγ ligands induce apoptosis in many cancers [17][18][19] and PGC-1α powerfully coactivates PPARγ [8], we asked whether PGC-1α-induced apoptosis in Ho-8910 cells is mediated by a PPARγ-dependent pathway.…”

“…PPARγ, a member of the nuclear receptor superfamily, forms a complex with coactivator PGCs to npg regulate gene expression [8,15,16]. PPARγ has a tumorigenic role in many kinds of cancers such as colon cancer [17,18] and mammary gland cancer [19], and activation of PPARγ signaling exacerbates the development of these tumors. On the other hand, PPARγ ligands have antiproliferative activity and induce apoptosis in many cancers [20][21][22].…”

Repression of β-catenin function in malignant cells by nonsteroidal antiinflammatory drugs

“…However, it is not clear how the functions of ␤-catenin, RXR-␣, and PPAR-␥ are connected. Indeed, some transgenic mice that express constitutively active PPAR-␥ have accelerated mammary gland tumors, compared with control animals from the same strains (40).…”