All-Trans-Retinoic Acid and the Glycolipid α-Galactosylceramide Combined Reduce Breast Tumor Growth and Lung Metastasis in a 4T1 Murine Breast Tumor Model

Vitamin A compounds are promising for cancer prevention and reducing risk of recurrence. Herein we have evaluated the combination of all-trans-retinoic acid (RA), a vitamin A metabolite, and alpha-galactosylceramide (alpha GalCer), a lipid immune activator, in Balb/C mice inoculated with syngeneic 4T1 breast tumor cells on reduction in breast tumor growth and lung metastasis. In Balb/c inoculated with the syngenic 4T1 primary tumor, and administered dendritic cells treated with RA + alpha GalCer, the size of the primary tumor and the number of lung metastatic foci were reduced. When 4T1 cells were introduced into the circulation as a model of hematogenous spread of tumor cells and RA and alpha CalCer were administered directly to mice without dendritic cells, lung metastatic foci were reduced 70% (P < 0.05), whereas each agent alone resulted in an intermediate decrease. Concomitantly, the expression of matrix metalloproteinases (MMP), membrane type-1 (MT1)-MMP and MMP3, were reduced by RA + alpha GalCer in lung. MMP3 protein was also reduced in plasma and culture supernatants from RA + alpha GalCer-treated 4T1 cells. Together, our results provide new evidence that a nutritional-immunological combination of RA + alpha GalCer may be promising for preventing or slowing the growth of metastatic foci, and suggest reduced MMP production as a possible mechanism.