Molecular Carcinogenesis 43: 198-205 He, G., S. Muga, P. Thuillier, R.A. Lubert, S.M. Fischer.

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Molecular Carcinogenesis 43: He, G., S. Muga, P. Thuillier, R.A. Lubert, S.M. Fischer

What is PPAR-  ? Peroxisome proliferator-activated receptor-gamma: member of the steroid nuclear hormone receptor superfamily Three types of PPAR, encoded by separate genes: , each with own set of prefered ligands PPAR-  ligands: Thiazolidone class of drugs (ciglitazone, triglitazone, rosiglitazone (Avandia- GSK, oral hypoglycemic drug) 15-dPGJ 2 Fatty acids PPAR-  has a role in adipocyte differentiation and fat metabolism.

Does PPAR-  have a role in carcinogenesis? Inhibit cancer: PPAR-  activators can inhibit growth of breast cancer cell lines in vitro by increasing sensitization to apoptosis. Reported to Inhibit in vivo growth in xenogeneic system (nude mice) and various in vivo cancer models. Promote cancer: Two reports that thiazolidone drugs promote colon cancer in animal models. Lisa’s data (J. Nutrition, 2005) is inconclusive: in vitro data indicates that PPAR-  inhibits tumor growth. In vivo data is another story- leans towards being pro-tumor (still a lot of questions). What about skin cancer?

PPAR-  in skin cancer PPAR-  +/- mice are more susceptible to DMBA-induced skin papilloma development compared to PPAR-g +/+ (wt) mice (Nicol et al, Carcinogenesis, 2004). In human skin, PPAR-  associated with keratinocyte differentiation: supra- basal cells only (Westergaard et al, JID, 2001). In vitro, PPAR-g ligands inhibit growth of cultured mouse keratinocytes. However, PPAR-  protein was not detected in the keratinocytes (He et al, JID,2004).

UV 3x/week for 15 weeks (90mJ/cm 2 start, increase 10% weekly to 175mJ/cm 2 ) Mice randomized to rosi+ or rosi- diet weeks (rosi 200ppm- very high compared to what Lisa uses- 12mg/kg) Tumors/mouse % mice with tumors No difference Effect of Dietary Rosiglitazone on UV Skin Carcinogenesis

Effect of Topical Troglitazone on UV carcinogenesis Tumors/mouse % mice with tumors UV 3x/week then topical treatment with 100  g troglitazone or acetone No significant effect

Effect of Dietary Rosi on DMBA/TPA skin carcinogenesis Tumors/mouse % mice with tumors FVB/n mice, shaved, 100  g DMBA, at 2 weeks, 3x/week treatment with 2.5  g TPA Mice randomized to rosi+ or rosi- diet weeks 2-17 (rosi 300ppm- very high compared to what Lisa uses- 12mg/kg) No significant effect

2000ppm troglitazone for 1 week TPA or vehicle, then inject with BrdU Inhibits control proliferation, but not TPA-induced proliferation Effect of dietary Troglitazone on BrdU labeling (epidermal proliferation)

PPAR-  mRNA (Northern blot) F= fat P=primary keratinocyte E= epidermis W= whole skin T= tumor FVB/N SKH

UV FVB/n 20X FVB/n 40X UV Skin tumor FVB/n 40X FVB/n (40X) From BrdU expt

UV FVB/n 20X FVB/n 40X UV Skin tumor UV skin tumor No section of normal SKH skin

Conclusions from this paper PPAR-  ligands did not significantly alter skin tumor development when used at ppm Lisa uses dietary Rosiglitazone and Fish oil to activate PPAR-  In breast cancer: Fish oil protective, PPAR-  does not appear to be protective (still trying to figure out what’s going on model specific (Her-2/neu Tg mice) dose of Rosi (12mg/kg vs 200ppm) In human studies, TGF-  induces PPAP-  and inhibits CTL restimulation. Further, PPAR-  ligand ciglitazone induces PPAR-  and alters APC function so that CTL restimulation is inhibited (Kelly’s expts) What about fish oil and Rosi in UV inflammation and carcinogenesis?

fish Fish+ rosi

** * * *

PPAR-  Fatty acids (LA,DHA,EPA) Breast cancer eicosanoids Fatty acid derivatives Thiazolidinediones (rosiglitazone) HER-2/neu+ Estrogen R Progesterone R RXR RAR Fat metabolism Adipocyte differentiation Cell proliferation, tumorigenesis