TREATMENT WITH CHEMOPREVENTIVE AGENTS, DIFLUOROMETHYLORNITHINE AND RETINYL ACETATE, RESULTS IN ALTERED MAMMARY EXTRACELLULAR-MATRIX

The effect of treatment with D-L-2-difluoromethylornithine (DFMO) plus retinyl acetate (RA) on the promotion stage of 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis was evaluated in female Sprague- Dawley rats. Combined treatment was more effective than single agent t reatment in decreasing cancer incidence and multiplicity and in prolon ging cancer latency, Increased efficacy was associated with reduced mo rphological complexity of the gland and increased mammary extracellula r matrix, Using ovarian hormones to model mitogen stimulation in the m ammary gland, DFMO plus RA treatment reduced mammary gland complexity in the absence of an effect on bromodeoxyuridine (BrDU) labeling index measured immunohistochemically. Morphological and biochemical evaluat ion of these glands revealed increased levels of extracellular matrix in rats treated with chemopreventive agents. Tenascin expression and f ibronectin levels were elevated and laminin levels were decreased, The fact that matrix degrading proteinase activity was also increased ind icated that tissue remodeling was modulated by these chemopreventive a gents. These data provide evidence of alterations in epithelial cell-e xtracellular matrix interactions that could account in part for the ch emopreventive effects of DFMO plus RA.