PPARdelta is pro-tumorigenic in a mouse model of COX-2-induced mammary cancer.
Cyclooxygenase-2 (COX-2), overexpressed in inflammatory conditions and cancer, regulates angiogenesis and tumorigenesis via the production of biologically active prostanoids. Previously, we showed that COX-2 over-expression in the mammary gland of transgenic mice induces an angiogenic switch and transforms the mammary epithelium into invasive mammary carcinoma. Since COX-2-derived prostanoids can activate the nuclear receptor PPARdelta, we crossed Ppardelta(-/-) mice with COX-2 transgenic mice in the FVB/N background. PPARdelta was expressed constitutively in the mammary gland of virgin, pregnant and lactating mice. Mammary hyperplasia and tumorigenesis in the COX-2 transgenic mice was markedly reduced in the Ppardelta(-/-) mice compared to their wild type counterparts. Analysis of the mammary tissues indicated that immunoreactive Ki-67, cyclin D1 and phosphorylated histone 3 (Phospho H3) were reduced in Ppardelta(-/-) mice, suggesting that PPARdelta activation regulates cell proliferation in the mammary gland. We postulate that activation of the nuclear receptor PPARdelta by COX-2-derived prostanoids may be involved in the proliferation of mammary epithelial cells and therefore contribute to mammary cancer development.
Ghosh
Mallika
M
Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030-3501, United States.
Ai
Youxi
Y
Narko
Kirsi
K
Wang
Zhenglong
Z
Peters
Jeffrey M
JM
Hla
Timothy
T
D000818:Animals; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D005260:Female; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D019394:Ki-67 Antigen / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D047494:PPAR delta / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D011453:Prostaglandins / Q000378:metabolism / Q000502:physiology
D006657:Histones; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D047494:PPAR delta; D011453:Prostaglandins; D019938:Cyclin D1; D051546:Cyclooxygenase 2