Dominant-Active Alleles of Rbi as Universal Tumor Suppressors of Mammary Carcinoma

摘要

The retinoblastoma tumor suppressor, Rb, regulates cellular proliferation, differentiation and survival, and is functionally inactivated by mutations or phosphorylation in most human cancers. While the activation of endogenous Rb by dephosphorylation is thought to provide an effective approach to suppress normal as well as neoplastic cell proliferation, the inhibition of apoptosis by Rb may have detrimental consequences in vivo. To test these paradigms, we targeted phosphorylation- resistant, constitutively active Rb alleles, Rb-DELTA-Ks, to the mouse mammary gland under control of the MMTV-LTR and WAP promoters. Here we show that pubescent MMTV-LTR-Rb-DELTA-Ks initially displayed reduced epithelial cell proliferation and delayed growth and branching of the ductal tree. Post-puberty transgenic mice exhibited alveolar outgrowth, precocious expression of the milk gene beta-Casein and extended survival of differentiated epithelial cells. Strikingly, multiple MMTV-LTR-Rb-DELTA-K and WAP-Rb-DELTA-K transgenic females developed focal preneoplastic lesions within 10-15 months and some presented with full-blown mammary adenocarcinoma. Expression of the Rb-DELTA-K transgene in these breast tumors was greatly reduced. The observations that both activation and inactivation of Rb can induce cancer in experimental mouse models, as is the case with its major partner, E2F1, have direct implications for cancer therapy.