Regulated Transformation of Mammary Epithelial Cells by Transforming Growth Factor Beta 1

摘要

We report that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed post-lactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Invading carcinoma cells in MMTV-DNIIR animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-Betas not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed. The ability of the TGF-beta signaling pathways to inhibit proliferation of many epithelial cells while stimulating proliferation fibroblasts remains a conundrum. We found that the absence of RhoA and p160(ROCK) activity in fibroblastic NIH3T3 cells and its presence in mammary epithelial NMuMG cells can at least partially explain the difference in the TGF- beta growth response. TGF-beta stimulation of pl60(ROCK)-mediated inactivation of the cdk-activating phosphatase, cdc25A, blocks G1-S progression in NMuMG cells. These results provide novel evidence that TGF-beta signaling through RhoA and pl60(ROCK) links signaling components for epithelial transdifferentiation with regulation of cell cycle progression.