THE CANCER GROWTH SUPPRESSOR GENE MDA-7 SELECTIVELY INDUCES APOPTOSISIN HUMAN BREAST-CANCER CELLS AND INHIBITS TUMOR-GROWTH IN NUDE-MICE

A differentiation induction subtraction hybridization strategy is bein g used to identify and clone genes involved in growth control and term inal differentiation in human cancer cells. This scheme identified mel anoma differentiation associated gene-7 (mda-7), whose expression is u pregulated as a consequence of terminal differentiation in human melan oma cells. Forced expression of mda-7 is growth inhibitory toward dive rse human tumor cells. The present studies elucidate the mechanism by which mda-7 selectively suppresses the growth of human breast cancer c ells and the consequence of ectopic expression of mda-7 on human breas t tumor formation ill vivo in nude mice. Infection of wild-type, mutan t, and null p53 human breast cancer cells with a recombinant type 5 ad enovirus expressing mda-7, Ad.mda-7 S, inhibited growth and induced pr ogrammed cell death (apoptosis). Induction of apoptosis correlated wit h an increase in BAX protein, an established inducer of programmed cel l death, and an increase in the ratio of BAX to BCL-2, an established inhibitor of apoptosis. Infection of breast carcinoma cells with Ad.md a-7 S before injection into nude mice inhibited tumor development. In contrast, ectopic expression of mda-7 did not significantly alter cell cycle kinetics, growth rate, or survival in normal human mammary epit helial cells. These data suggest that mda-7 induces its selective anti cancer properties in human breast carcinoma cells by promoting apoptos is that occurs independent of p53 status. On the basis of its selectiv e anticancer inhibitory activity and its direct antitumor effects, mda -7 may represent a new class of cancer suppressor genes that could pro ve useful for the targeted therapy of human cancer.