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Peroxisome Proliferator-Activated Receptor Activation during Pregnancy Severely Impairs Mammary Lobuloalveolar Development in Mice

Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Frank J. Gonzalez, Building 37, Room 3106B, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892. E-mail: fjgonz{at}helix.nih.gov.

To identify the potential functions of peroxisome proliferator-activated receptor (PPAR) in skin development, transgenic mice were generated to target constitutively activated PPAR (VP16PPAR) to the stratified epithelia by use of the keratin K5 promoter. In addition to marked alterations in epidermal development, the transgenic mice had a severe defect in lactation during pregnancy resulting in 100% pup mortality. In this study, the alteration of mammary gland development in these transgenic mice was investigated. The results showed that expression of the VP16PPAR transgene during pregnancy resulted in impaired development of lobuloalveoli, which is associated with reduced proliferation and increased apoptosis of mammary epithelia. Mammary epithelia from transgenic mice also showed a significant reduction in the expression of ß-catenin and a down-regulation of one of its target genes, cyclin D1, which is thought to be required for lobuloalveolar development. Furthermore, upon PPAR ligand treatment, similar effects on lobuloalveolar development were observed in wild-type mice, but not in PPAR-null mice. These findings suggest that PPAR activation has a marked influence in mammary lobuloalveolar development.

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