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Retinoids induce MMP-9 expression through RAR during mammary gland remodeling

¹Departamento de Bioquímica y Biología Molecular, ²Departamento de Medicina, and ³Unidad Central de Investigación, Facultad de Medicina-Fundación Investigación Hospital Clínico Valencia, Universidad de Valencia, Valencia, Spain

Submitted 4 September 2006 ; accepted in final form 1 December 2006

Retinoic acid (RA) is a signaling molecule in the morphogenesis of the mammary gland, modulating the expression of matrix metalloproteinases (MMPs). The aim of this paper was to study the role of RA during weaning, which consists of three events: apoptosis of the secretory cells, degradation of the extracellular matrix, and adipogenesis. CRABP II and CRBP-1 carrier proteins increased significantly during weaning compared with lactating glands but reverted to control values after the litter resuckled. The effects of RA are mediated by the nuclear receptors RAR, RAR, RAR, and RXR, which underwent an increase in protein levels during weaning. In an attempt to elucidate the RAR-dependent signaling pathway, ChIP assays were performed. The results showed the binding of RAR to the MMP-9 promoter after 24- and 72-h weaning together with its coactivator p300; this fact could be responsible for the increase found in MMP-9 mRNA and protein levels in these conditions. Expression of related MMPs (MMP-2 and MMP-3) was also increased during weaning. Using gelatine zymography, we observed a time-dependent increase in active forms of MMP-9 and MMP-2. On the other hand, the inhibitor of MMPs, TIMP-1, was almost undetectable at 24- and 72-h weaning by Western blot. The role of retinoids in matrix remodeling is reinforced by the fact that administration of an acute dose of retinol palmitate to control lactating rats also induces MMP-9 expression. This emphasizes the importance of retinoids in vivo to regulate mammary gland involution.

mammary gland involution; matrix metalloproteinase-9; stromelysin-1; retinoic acid; retinoid acid receptor-

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