INDUCTION OF A LESS AGGRESSIVE BREAST-CANCER PHENOTYPE BY PROTEIN-KINASE C-ALPHA AND C-BETA OVEREXPRESSION

To address the isoenzyme-specific involvement of protein kinase C (PKC ) in breast cancer biology, hormone-responsive MCF-7 breast cancer cel ls were infected with either PKC-alpha or -beta(1) cDNAs subcloned in the retroviral expression vector pMV7, Several stable clones of PKC-ov erexpressing cells were generated. Western analysis revealed cross-reg ulation between the alpha and beta isoforms, because induction of over expression of one up-regulated the other, Overexpression of the alpha and beta isoenzymes, on the other hand, did not affect the already hig h endogenous expression of the novel delta, epsilon, eta, and zeta iso forms, Compared with control clones, PKC-alpha and -beta-overexpressin g MCF-7 cells exhibited more drastic morphological changes in response to phorbol 12-myristate 13-acetate administration characterized by ce llular flattening and vacuolization, More importantly, induction of PK C-alpha and -beta overexpression induced a less aggressive biological behavior, which was characterized by reduced in vitro invasiveness and markedly diminished tumor formation and growth in nude mice, These in vivo findings can probably best be explained by the dramatic down-reg ulation of estrogen receptor levels observed in tumors derived from PK C-alpha-infected MCF-7 cells, Our data clearly show that it is possibl e to induce a less aggressive breast cancer phenotype by altering PKC isoenzyme expression.