Active Rb causes nodule formation.

Caution and more experiments are in order, say Jiang and Zacksenhaus (page 185), for drug companies hoping to activate the Rb pathway with anticancer compounds. The authors have found that expression of a constitutively active version of the tumor suppressor Rb can result in the counterintuitive outcome of more tumor formation.

Initially, expression of activated Rb in transgenicmice does suppress cell proliferation somewhat. But Jiang and Zacksenhaus suggest that this growth suppression may also positively select for cells with transforming mutations. Usually most cells with such mutations would be eliminated by apoptosis. But Rb is known to suppress apoptosis, and this appears to occur in the transgenic mice. In mammary tissue, where the tumors are eventually seen, apoptosis during involution is reduced by 44%.

This failure in apoptosis may give rise to the focal hyperplastic nodules that the authors see in approximately one third of the transgenic animals. The large tumors that finally arise are fewer in number than these nodules, and no longer express the activated Rb transgene, suggesting that extinction of Rb expression may be at least one of the steps leading to final transformation.

Mammary tissue may be particularly susceptible to such a tumor-formation pathway because a large proportion of the epithelium turns over during each estrous cycle, as the tissue is prepared for a potential pregnancy and then restored to its former state. Similar problems may arise in human tissues that remodel extensively, such as breast, ovary, and endometrium. Zacksenhaus suggests, therefore, that antiproliferative drugs should be paired with proapoptotic drugs in new combinatorial drug trials. ▪